The Synergistic Roles of Glial Cells and Non-Coding RNAs in the Pathogenesis of Alzheimer’s Disease and Related Dementias (ADRDs)

Abstract

This review synthesizes the emerging understanding of the roles of glial cells and non-coding RNAs (ncRNAs) in the pathogenesis and progression of Alzheimer’s disease and related dementias (ADRDs). ADRDs encompass a spectrum of neurodegenerative disorders characterized by cognitive decline, memory impairment, and functional deterioration. The interplay between the most common types of glial cells—astrocytes, microglia, and oligodendrocytes—and ncRNAs is emerging as a critical factor in the development of ADRDs. Glial cells are essential for maintaining homeostasis within the central nervous system (CNS); however, their dysregulation can lead to neuroinflammation and neuronal dysfunction, exacerbating neurodegeneration. Reactive astrocytes and activated microglia can create neurotoxic environments that further impair neuronal health. Concurrently, ncRNAs, particularly long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), have emerged as significant regulators of glial gene expression, influencing inflammatory responses and glial cell function. Understanding the complex interactions between glial cells and ncRNAs is crucial for developing targeted therapeutic strategies. By elucidating the mechanisms underlying their interactions, this review aims to highlight the critical importance of glial cells and ncRNAs in the context of neurodegenerative diseases, paving the way for innovative approaches to prevent and treat ADRDs. Ultimately, enhancing our understanding of these processes may lead to novel therapies and improved outcomes for individuals affected by these debilitating conditions.

1. Introduction

Alzheimer’s disease and related dementias (ADRDs) encompass a spectrum of neurodegenerative disorders characterized by progressive cognitive decline, memory impairment, and functional deterioration. Among these, Alzheimer’s disease (AD), frontotemporal dementia (FTD), Lewy body dementia (LBD), vascular contributions to cognitive impairment and dementia (VCID), and multiple etiology dementia (MED) represent the most significant and common forms of dementia. Each of these conditions exhibits distinct clinical features, underlying pathophysiology, and implications for diagnosis and management.

1.1. Overview of ADRDs

Alzheimer’s disease, the most prevalent form of dementia, accounts for approximately 60–80% of all dementia cases [1]. AD is primarily characterized by progressive memory loss, language difficulties, and impaired reasoning abilities. Neuropathologically, AD is marked by the accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein, leading to neuronal loss and brain atrophy [2,3]. The clinical trajectory typically begins with mild cognitive impairment, which can progress to more severe cognitive deficits, ultimately affecting daily functioning, independence and overall quality of life [4]. The prevalence of AD is projected to rise significantly, with estimates suggesting that by 2060, around 14 million individuals in the United States will be living with the disease [5,6].

Frontotemporal dementia, while less common than AD, constitutes a significant subset of ADRDs, particularly among younger individuals. Unlike AD, FTD typically affects individuals in their 50 s and 60 s, presenting unique challenges for patients and their families [7]. FTD is characterized by progressive changes in personality, behavior, and language, often preceding memory loss [8]. The underlying pathology involves degeneration of the frontal and temporal lobes of the brain, which can manifest in various clinical syndromes, including behavioral variant FTD and primary progressive aphasia [9]. These syndromes highlight the diverse presentations of FTD, complicating diagnosis and management [10].

Lewy body dementia represents another critical form of ADRDs, distinguished by the presence of Lewy bodies—abnormal protein aggregates composed of alpha-synuclein—in the brain. LBD can present with fluctuating cognition, visual hallucinations, and parkinsonism, making it particularly challenging to differentiate from both AD and Parkinson’s disease [11]. The overlap of symptoms can lead to misdiagnosis, impacting treatment decisions and care strategies. Patients with LBD may experience significant fluctuations in attention and alertness, further complicating their clinical management [12]. Recognizing LBD as a distinct entity within the spectrum of ADRDs is essential for appropriate therapeutic approaches and caregiver support [13].

Vascular contributions to cognitive impairment and dementia (VCID) represent a significant but often under-recognized aspect of ADRDs. VCID arises from cerebrovascular disease, leading to reduced blood flow to the brain (hypoperfusion) and subsequent cognitive decline. This form of dementia can result from multiple small strokes or chronic ischemia and is frequently associated with vascular risk factors such as hypertension and diabetes [14]. The clinical presentation of VCID can vary widely, often overlapping with symptoms of AD and other dementias, complicating diagnosis [15]. Effective management of VCID requires addressing the underlying vascular risk factors to prevent further cognitive decline [16].

Multiple-etiology dementia (MED) refers to the coexistence of multiple types of dementia pathology, most commonly AD and vascular dementia [17]. This condition is increasingly recognized as a prevalent form of dementia among older adults, as many individuals exhibit overlapping features of different dementias [18]. The presence of mixed pathology can influence the clinical course and response to treatment, necessitating a comprehensive approach to diagnosis and management [19]. Understanding the interplay between different dementia types is crucial for developing effective therapeutic strategies and optimizing patient outcomes [20].

The growing prevalence of ADRDs poses significant challenges for healthcare systems, caregivers, and society at large. The economic burden associated with these conditions is substantial, encompassing costs related to medical care, long-term care, and lost productivity [21]. Furthermore, the emotional and psychological toll on caregivers is profound, as they navigate the complexities of providing care for individuals with progressive cognitive decline [22]. Addressing the needs of both patients and caregivers is essential for improving quality of life and ensuring effective support systems are in place [23].

1.2. Glial Cells in ADRDs

In recent years, the role of glial cells—specifically astrocytes, microglia, and oligodendrocytes—in the pathophysiology of ADRDs has garnered increasing attention. Astrocytes, the most abundant glial cell type in the CNS, provide structural, metabolic, and trophic support to neurons. They are involved in neurotransmitter uptake, ion homeostasis, and the maintenance of the blood–brain barrier [24,25]. However, in the context of neurodegeneration, astrocytes can undergo reactive changes that contribute to neuronal dysfunction. Reactive astrocytes release pro-inflammatory cytokines and neurotoxic factors, exacerbating neuroinflammation and promoting neuronal death [26,27]. Studies have shown that astrocytic dysfunction is linked to the progression of ADRDs, where astrocytes lose their neuroprotective functions and instead adopt neurotoxic properties [28,29,30,31,32,33]. This duality of astrocytic function underscores the complexity of their role in neurodegenerative processes.

Microglia, the resident immune cells of the central nervous system, play an integral role in both maintaining homeostasis and driving pathological processes in neurodegeneration. These cells continuously monitor the brain environment and are largely responsible for removing cellular debris. However, their activation frequently transitions into a pro-inflammatory state that exacerbates neurodegenerative pathology [34]. Research indicates that microglial activation substantially impacts astrocytic function, establishing a reciprocal interaction that amplifies neuroinflammatory signaling and accelerates neuronal damage [35,36]. For example, activated microglia have been shown to induce a neurotoxic phenotype in astrocytes, further propagating inflammation and neurotoxicity [37,38]. This dynamic underscores the necessity of elucidating glial cell crosstalk within the pathophysiological framework of ADRDs.

Oligodendrocytes, while primarily known for their role in myelination, also contribute to neuronal health and function. They provide metabolic support to axons and are involved in the maintenance of axonal integrity [24,25]. In neurodegenerative diseases, oligodendrocyte dysfunction leads to demyelination, thereby exacerbating the progression of cognitive decline. Emerging evidence suggests that oligodendrocytes may also respond to inflammatory signals from astrocytes and microglia, further complicating the cellular dynamics in ADRDs [24,25].

The role of glial cells in the pathogenesis of ADRDs holds particular significance when examining the mechanisms underlying neuroinflammation and neurodegeneration. For instance, astrocytes are known to secrete factors that regulate neuronal survival and function, including neurotrophic factors and cytokines [24,25]. However, in the context of neurodegeneration, the balance of these secreted factors shifts towards a neurotoxic profile, leading to increased neuronal vulnerability [26,27]. Additionally, astrocytes sustain neuronal function by regulating the metabolic microenvironment through the provision of essential nutrients and energy substrates, while disruptions in this support are implicated in the acceleration of neurodegenerative processes [24,25].

When considering these glial cell contributions to neurodegeneration, it is crucial to understand their temporal dynamics across ADRD progression. Current evidence suggests that glial reactivity, particularly microglial activation, represents one of the earliest detectable cellular responses in ADRDs, often preceding symptom onset and significant neuronal loss [39]. In AD, microglial activation and associated neuroinflammatory changes can be detected in the prodromal and mild cognitive impairment (MCI) stages, suggesting these processes may contribute to disease initiation rather than simply responding to established pathology [40]. Astrocytic reactivity follows a similar pattern, with early morphological and functional changes detectable in preclinical and early symptomatic phases [41]. In contrast, oligodendrocyte dysfunction appears to accumulate gradually throughout disease progression, with more pronounced effects in later stages that correlate with cognitive decline severity [42]. This temporal progression of glial dysfunction provides an important context for understanding both disease mechanisms and potential therapeutic windows, as interventions targeting early glial changes may offer greater neuroprotective benefits before extensive damage occurs [43].

1.3. Non-Coding RNAs in ADRDs

In addition to glial cells, non-coding RNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and transposable elements, have emerged as significant players in ADRDs. For example, non-coding RNAs are involved in regulating glial gene expression and cellular responses, influencing both neuroinflammation and neurodegeneration. miRNAs can modulate the expression of pro-inflammatory cytokines in glial cells, thereby affecting the inflammatory response in neurodegenerative diseases [44]. Furthermore, lncRNAs have been implicated in the regulation of glial cell function and neuronal health, with dysregulation of these molecules potentially contributing to the pathogenesis of ADRDs [45]. Transposable elements (TEs), which are sequences of DNA capable of moving within the genome, have been implicated in Alzheimer’s disease (AD) through their potential to disrupt genomic stability and contribute to neuroinflammation [46]. Often considered “junk” DNA, TEs have gained attention for their role in neurodegenerative diseases [47]. Recent studies suggest that the activation of transposable elements during aging leads to the production of double-stranded RNA (dsRNA), which may trigger neuroinflammation and contribute to neuronal death [48,49]. Additional mechanisms include the activation of the brain’s immune system, exacerbating neurodegenerative processes, and may also promote the accumulation of toxic proteins such as amyloid-β, further accelerating AD pathology [50].

As the understanding of ADRDs continues to evolve, there is increasing recognition of the intricate roles played by glial cells and non-coding RNAs in the pathogenesis and progression of these neurodegenerative disorders. Glial cells are not merely supportive elements within the central nervous system; they actively participate in neuroinflammatory processes, neuronal health, and the maintenance of homeostasis. Recent research has illuminated the dual nature of glial cells, where reactive changes can lead to neurotoxic environments that exacerbate neuronal dysfunction and contribute to the progression of ADRDs [51]. Understanding the molecular mechanisms underlying these interactions is crucial for developing targeted therapeutic strategies. In parallel, non-coding RNAs, such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and transposable elements, have emerged as significant regulators of gene expression and cellular responses in the context of neurodegeneration. These non-coding RNAs are involved in various processes, including the modulation of inflammatory responses, regulation of glial cell function, and neuronal survival. For instance, specific miRNAs are implicated in the dysregulation of glial cell activation and the propagation of neuroinflammation, while studies demonstrate that lncRNAs influence glial differentiation and function. Additionally, transposable elements can disrupt genomic stability and contribute to the pathophysiological landscape of ADRDs [52]. The interplay between glial cells and non-coding RNAs represents a complex regulatory network that warrants comprehensive exploration.

This review aims to consolidate the current knowledge surrounding the interplay between glial cells and non-coding RNAs in the pathogenesis and progression of ADRDs. By examining the mechanisms by which these cellular and molecular players interact, we hope to elucidate their contributions to neuroinflammation, neuronal health, and disease. Furthermore, we will explore potential therapeutic avenues that target these interactions, with the goal of advancing our understanding and treatment of ADRDs. We aim to provide a comprehensive overview that highlights the critical importance of glial cells and non-coding RNAs in the context of neurodegenerative diseases.

To begin, we will outline the role of astrocytes in the five major ADRDs (AD, FTD, LBD, VCID, and MED). While each of these conditions is associated with distinct pathogenic features, there is a common thread of astrocytic dysfunction. Understanding how astrocytes respond to these pathological insults provides crucial insights into their role in neurodegeneration and highlights the potential for targeting astrocytic pathways to ameliorate disease progression.

Having established the multifaceted roles of glial cells in the pathophysiology of ADRDs, we will first examine astrocytes, the most abundant glial cell type in the CNS. Astrocytes serve as key regulators of neuronal homeostasis through their extensive functions in neurotransmitter recycling, ion balance, and blood–brain barrier maintenance. Understanding how these cells undergo pathological transformations across different ADRDs provides crucial insights into disease progression and potential therapeutic targets.

Having established the complex landscape of ADRDs and the emerging importance of glial cells in their pathogenesis, we will now examine each major glial cell type and its contributions to neurodegenerative processes. We begin with astrocytes, the most abundant glial cells in the CNS, which provide essential support for neuronal function and homeostasis. While each ADRD presents with distinct pathogenic features, astrocytic dysfunction represents a common thread across these conditions, often emerging in early disease stages. Understanding how these cells respond to pathological insults across different ADRDs provides crucial insights into disease mechanisms and reveals potential therapeutic targets for intervention before extensive neurodegeneration occurs.

2. Astrocytes

Astrocytes, a vital component of the central nervous system (CNS), play critical roles in maintaining homeostasis through functions such as regulating the blood–brain barrier (BBB), neurotransmitter recycling, and extracellular ion balance [53,54]. In ADRDs, astrocytes undergo a pathological transformation into reactive states, a process known as reactive astrogliosis [55]. This transition involves significant morphological, functional, and transcriptional changes, which not only impair their protective roles but also exacerbate neuroinflammation, synaptic dysfunction, and neuronal loss [56,57].

2.1. Astrocyte Morphological Changes

Reactive astrocytes in ADRDs exhibit hypertrophy and increased ramification, reflecting their transition from a homeostatic to a reactive phenotype [58,59]. In AD, astrocytes cluster around amyloid-β (Aβ) plaques, displaying enlarged cell bodies and thickened processes [60,61]. This morphological response is accompanied by the loss of astrocytic end-feet, which disrupts BBB integrity and allows peripheral immune cell infiltration, exacerbating neuroinflammation [62,63].

Similar morphological changes are observed in FTD, where reactive astrocytes are linked to tau pathology [64,65]. These cells exhibit swollen, hypertrophic processes and a fragmented structure, impairing their interactions with neurons and exacerbating tau-mediated damage [66,67]. In LBD, astrocytes respond to α-synuclein aggregates with hypertrophy and abnormal process remodeling, further disrupting synaptic and vascular support6566.

In VCID, chronic hypoperfusion induces widespread astrogliosis, with hypertrophic astrocytes losing their structural association with blood vessels [68,69]. This compromises their role in BBB maintenance and amplifies vascular permeability [27,70]. MEDs, which combine neurodegenerative and vascular pathologies, exhibit more severe astrocytic hypertrophy and process fragmentation. This increased severity results from the combined insults of Aβ deposition and ischemic injury [71,72].

2.2. Astrocyte Functional Impairments

Astrocytic dysfunction in ADRDs significantly disrupts their homeostatic roles, driving Astrocytic dysfunction in ADRDs significantly disrupts their homeostatic roles, driving inflammation and neuronal damage [73,74]. Across these conditions, reactive astrocytes release elevated levels of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) [75,76]. These cytokines propagate neuroinflammation and exacerbate neuronal vulnerability [20,77].

Reactive astrocytes also show dysregulated chemokine production, including elevated levels of CCL2 (MCP-1), CCL5 (RANTES), and CXCL10 (IP-10) [78,79]. These chemokines attract immune cells to sites of injury, further intensifying inflammation [80,81]. Additionally, reactive astrocytes release matrix metalloproteinases (MMPs), which degrade the extracellular matrix and compromise synaptic integrity, particularly in AD and LBD [82,83].

Additionally, impaired Aβ clearance by astrocytes represents a critical functional deficit that contributes to amyloid plaque accumulation in AD. Several molecular mechanisms that underlie this impairment have been proposed. First, reactive astrocytes show decreased expression of Aβ-degrading enzymes such as neprilysin (NEP) and insulin-degrading enzyme (IDE), reducing their capacity to enzymatically process Aβ peptides [84]. Second, the low-density lipoprotein receptor-related protein 1 (LRP1), a key receptor mediating Aβ uptake and clearance, is downregulated in AD astrocytes, further limiting their ability to internalize Aβ [85]. Third, the ATP-binding cassette transporter A1 (ABCA1), which facilitates Aβ clearance through ApoE lipidation, shows reduced functionality in reactive astrocytes [86]. Additionally, AD astrocytes exhibit impaired lysosomal degradation pathways, including defective autophagy and reduced lysosomal acidification, which compromises their ability to degrade internalized Aβ [87]. The ApoE ε4 allele further exacerbates these deficits by reducing astrocytic Aβ clearance efficiency compared to other ApoE isoforms, providing a mechanistic link between this genetic risk factor and impaired Aβ proteostasis [88].

Furthermore, in ADRDs, astrocytes fail to regulate glutamate homeostasis, contributing to excitotoxicity [89]. Impaired glutamate uptake, due to the reduced expression or dysfunction of transporters such as GLT-1 leads to excessive extracellular glutamate levels [90,91]. This excitotoxicity damages neurons and synapses, particularly in AD, FTD, and LBD [92,93]. The loss of astrocytic end-feet in ADRDs further compromises BBB integrity [94,95]. In AD, FTD, LBD, and VCID, BBB disruption allows peripheral immune cells and neurotoxic substances to infiltrate the CNS, aggravating inflammation and neuronal damage [96,97]. MEDs demonstrate compounded BBB dysfunction due to overlapping pathological mechanisms [98,99].

2.3. Astrocyte Transcriptional Alterations

Astrocytic transcriptional profiles in ADRDs reflect extensive reprogramming associated with inflammation, oxidative stress, and metabolic dysfunction [100,101]. Across ADRDs, upregulation of genes linked to the NF-κB pathway drives cytokine production (e.g., IL-1β and IL-6) and inflammasome activation (e.g., NLRP3) [53,54]. These transcriptional changes perpetuate neuroinflammation and impair glutamate homeostasis [55,102].

In AD and LBD, astrocytes show transcriptional dysregulation of genes involved in Aβ and α-synuclein clearance, respectively [56,57]. Reduced expression of genes critical for lysosomal function further hinders the degradation of these aggregates, exacerbating neurotoxicity [58,59]. In FTD, astrocytes upregulate IL-6-related signaling pathways and genes promoting tau aggregation, linking transcriptional reprogramming to tau pathology [60,61]. VCID astrocytes display increased expression of hypoxia-related genes and pathways such as AIM2 inflammasome signaling, highlighting their role in ischemia-induced damage [62,63].

Genetic factors also play a pivotal role in astrocytic dysfunction. In AD, mutations in APP, PSEN1, and PSEN2 increase Aβ accumulation, triggering astrocyte activation [64,65]. The ApoE ε4 allele enhances astrocytic reactivity, promoting inflammation and impairing lipid transport [66,67]. FTD-associated mutations in MAPT and GRN disrupt tau clearance and exacerbate inflammatory signaling [103,104]. In LBD, GBA mutations impair astrocytic lysosomal function, facilitating α-synuclein aggregation [68,69]. In VCID and MEDs, APOE ε4 and C9orf72 mutations amplify astrocytic reactivity, compounding vascular and neurodegenerative damage [27,70].

In conclusion, astrocytes play a pivotal role in the progression of various dementias, where their dysfunction contributes to neuroinflammation, neuronal damage, and cognitive decline (Figure 1, Table 1). In ADRDs, reactive astrogliosis alters astrocytic functions, including the secretion of pro-inflammatory cytokines, chemokines, and the disruption of the blood-brain barrier. The extensive analysis of astrocytic contributions to ADRD pathogenesis illustrates how these traditionally supportive cells can become key drivers of neuroinflammation and neurodegeneration when their homeostatic functions are compromised. However, astrocytes do not respond to pathological insults in isolation. Their activation states and functional outputs are intimately linked to other glial populations, particularly microglia, with whom they engage in continuous bidirectional communication.

Microglia, as the resident immune cells of the CNS, represent the next critical population in our examination of glial contributions to ADRDs. Unlike astrocytes, which derive from neural progenitors, microglia originate from yolk sac-derived myeloid precursors and enter the CNS during early development, establishing themselves as the primary mediators of innate immunity within the brain [105,106]. Under physiological conditions, these highly ramified cells continuously survey their microenvironment, rapidly responding to disturbances in CNS homeostasis [107]. The distinctive ontogeny and immune functions of microglia position them as key responders to the protein aggregates, cellular damage, and inflammatory signals characteristic of ADRDs. The following section will explore how microglial activation states evolve throughout disease progression, their disease-specific responses across different ADRDs, and how their interactions with astrocytes create complex inflammatory environments that influence neuronal health and cognitive outcomes.

Table 1. Summary of the morphological changes, functional impairments, and transcriptional alterations of astrocytes in ADRDs.

	Morphological Changes	Functional Impairments	Transcriptional Alterations
All ADRDs	Hypertrophy [58,59] Increased ramification [58,59] Loss of end-feet disrupts the BBB [94,95] Increased vascular permeability, neuroinflammation [96,97]	Pro-inflammatory cytokine/chemokine release [75,76,77] Impaired glutamate uptake [83,89] Excitotoxicity [92,93] MMP release damages synapses and the extracellular matrix [82]	NF-κB pathway upregulation [53,54] Genetic mutations amplify reactivity and impair glutamate homeostasis [55,102]
AD	Cluster around amyloid-β plaques [60,61] Enlarged cell bodies and thickened processes [60,61] Severe BBB disruption [62,63]	Impaired amyloid-β clearance [60,61] Exacerbated neurotoxicity and synaptic damage [60,61]	Dysregulated amyloid-β clearance genes (APP, PSEN1, and PSEN2) [56,64,65] Reduced lysosomal function exacerbates toxicity [58,59] ApoE ε4 impairs lipid transport [66,67]
FTD	Linked to tau pathology [64,65] Fragmented, hypertrophic astrocytes [66,67]	Tau-mediated damage [64,65] Exacerbated inflammation and synaptic dysfunction [64,65]	Upregulated tau aggregation pathways (MAPT and GRN) [57] IL-6 signaling contributes to pathology [60,61]
LBD	Response to α-synuclein aggregates [103,104] Process remodeling disrupts support [103,104]	Impaired α-synuclein clearance [103,104] Synaptic dysfunction from excitotoxicity and MMP release [103,104]	Dysregulated α-synuclein clearance genes [68,69] GBA mutations worsen lysosomal dysfunction [68,69]
VCID	Widespread astrogliosis [68,69] Loss of vascular association amplifies permeability [27,70]	Hypoxia-induced BBB disruption [94,95]	Upregulation of hypoxia-related genes [62] AIM2 inflammasome signaling worsens damage [63]
MEDs	Severe hypertrophy and fragmentation [71,72] Combined amyloid-β deposition & ischemic injury [71,72]	Overlapping vascular & neurodegenerative effects [98,99] BBB and synaptic damage compounded [98,99]	Shared transcriptional features of AD andVCID [27,70] Amplified by genetic and ischemic insults (C9orf72 and ApoE ε4) [27,70]

Table 1. Summary of the morphological changes, functional impairments, and transcriptional alterations of astrocytes in ADRDs.

	Morphological Changes	Functional Impairments	Transcriptional Alterations
All ADRDs	Hypertrophy [58,59] Increased ramification [58,59] Loss of end-feet disrupts the BBB [94,95] Increased vascular permeability, neuroinflammation [96,97]	Pro-inflammatory cytokine/chemokine release [75,76,77] Impaired glutamate uptake [83,89] Excitotoxicity [92,93] MMP release damages synapses and the extracellular matrix [82]	NF-κB pathway upregulation [53,54] Genetic mutations amplify reactivity and impair glutamate homeostasis [55,102]
AD	Cluster around amyloid-β plaques [60,61] Enlarged cell bodies and thickened processes [60,61] Severe BBB disruption [62,63]	Impaired amyloid-β clearance [60,61] Exacerbated neurotoxicity and synaptic damage [60,61]	Dysregulated amyloid-β clearance genes (APP, PSEN1, and PSEN2) [56,64,65] Reduced lysosomal function exacerbates toxicity [58,59] ApoE ε4 impairs lipid transport [66,67]
FTD	Linked to tau pathology [64,65] Fragmented, hypertrophic astrocytes [66,67]	Tau-mediated damage [64,65] Exacerbated inflammation and synaptic dysfunction [64,65]	Upregulated tau aggregation pathways (MAPT and GRN) [57] IL-6 signaling contributes to pathology [60,61]
LBD	Response to α-synuclein aggregates [103,104] Process remodeling disrupts support [103,104]	Impaired α-synuclein clearance [103,104] Synaptic dysfunction from excitotoxicity and MMP release [103,104]	Dysregulated α-synuclein clearance genes [68,69] GBA mutations worsen lysosomal dysfunction [68,69]
VCID	Widespread astrogliosis [68,69] Loss of vascular association amplifies permeability [27,70]	Hypoxia-induced BBB disruption [94,95]	Upregulation of hypoxia-related genes [62] AIM2 inflammasome signaling worsens damage [63]
MEDs	Severe hypertrophy and fragmentation [71,72] Combined amyloid-β deposition & ischemic injury [71,72]	Overlapping vascular & neurodegenerative effects [98,99] BBB and synaptic damage compounded [98,99]	Shared transcriptional features of AD andVCID [27,70] Amplified by genetic and ischemic insults (C9orf72 and ApoE ε4) [27,70]

3. Microglia

Microglia, the resident immune cells of the central nervous system (CNS), are indispensable for maintaining neural homeostasis. These cells continuously surveil their microenvironment, responding dynamically to injury, infection, and disease [97,98]. In ADRDs, microglial activation emerges early and persists as a driver of pathology [99,100]. Upon activation, microglia exhibit profound morphological, molecular, and functional changes, leading to the release of pro-inflammatory cytokines, chemokines, and reactive oxygen species (ROS) [101,102]. While this response is vital for debris clearance and neuronal support under normal conditions, its dysregulation in ADRDs establishes a chronic inflammatory state that accelerates neurodegeneration [103,104].

3.1. Microglial Morphological Changes

Activated microglia across ADRDs are characterized by hypertrophy, increased ramification, and process retraction, reflecting their transition from a homeostatic to a reactive state [108,109]. In AD, microglia cluster around amyloid-β (Aβ) plaques, adopting a dystrophic morphology with fragmented processes and rounded cell bodies [110,111]. These dystrophic microglia are less effective at clearing plaques and contribute to chronic inflammation, exacerbated by pro-inflammatory cytokines such as IL-1β and TNF-α [112,113,114]. This persistent activation has been linked to neurodegeneration, highlighting the dual role of microglia as both protectors and contributors to neurodegenerative processes [115].

Similar morphological changes are observed in FTD, where hypertrophic microglia are associated with tau pathology [116,117]. These cells often display disorganized processes, which compromise their interactions with neurons and exacerbate tau-mediated neurotoxicity [118,119]. In LBD, α-synuclein aggregates induce microglial hyper-ramification, impairing synaptic support and promoting oxidative stress, which contributes to dopaminergic neuron loss [120]. This suggests that microglial activation in LBD may play a role in disease progression rather than merely responding to neuronal damage [121].

In VCID, chronic ischemia triggers microglial activation, leading to hypertrophy and the loss of processes critical for maintaining neurovascular unit integrity [122]. MEDs exhibit amplified morphological abnormalities, with microglial hypertrophy and widespread structural dysfunction contributing to blood–brain barrier (BBB) breakdown and neuronal injury [123,124]. Recent studies indicate that microglial activation varies significantly across different neurodegenerative diseases and stages, suggesting that the underlying pathological substrates influence microglial behavior [125]. Understanding these dynamics is crucial for elucidating the role of microglia in ADRDs and their interactions with neurons and other glial cells [126].

3.2. Microglial Functional Impairments

Microglial activation in ADRDs disrupts their homeostatic roles, driving chronic inflammation and neuronal damage [127,128]. Across all ADRDs, microglia release elevated levels of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) [129]. These cytokines exacerbate neuronal injury, impair synaptic function, and perpetuate neurotoxic feedback loops with other glial cells, particularly astrocytes [129,130].

Dysregulated chemokine production is also a hallmark of microglial activation. In AD, FTD, and LBD, elevated levels of CCL2 (MCP-1), CCL5 (RANTES), and CXCL10 (IP-10) are observed, promoting peripheral immune cell recruitment and intensifying neuroinflammation [131,132]. This chemokine dysregulation further amplifies microglial activation, creating a self-sustaining inflammatory cycle [133,134].

Microglia exhibit several molecular mechanisms of impaired Aβ clearance in AD. First, the downregulation of Aβ-binding receptors, including triggering receptor expressed on myeloid cells 2 (TREM2), CD36, and Toll-like receptors (TLRs), reduces the microglial capacity for Aβ recognition and phagocytosis [135]. TREM2 dysfunction is particularly significant, as TREM2 variants are established risk factors for AD, and TREM2 signaling is essential for microglial phagocytic activity and metabolic fitness around amyloid plaques [136]. Second, chronic exposure to Aβ induces microglial immune tolerance and dysfunction of the lysosomal-autophagy system, impairing the degradation of internalized Aβ [137]. Third, pro-inflammatory cytokines such as TNF-α and IL-1β, which are elevated in AD, inhibit microglial phagocytic capacity while promoting a neurotoxic phenotype [138]. Additionally, microglia in AD show decreased expression of Aβ-degrading enzymes, including neprilysin and the insulin-degrading enzyme. The ApoE ε4 allele further suppresses microglial Aβ clearance through altered lipid metabolism and inflammatory signaling, providing another mechanism by which this genetic risk factor contributes to AD pathogenesis [139].

ROS production by microglia is another shared feature across ADRDs, contributing to oxidative stress and mitochondrial dysfunction in neurons [123,140]. In LBD and VCID, oxidative damage is exacerbated by impaired microglial support for synaptic and vascular structures, leading to synaptic disintegration and BBB compromise [119,141].

Microglia also exhibit impaired clearance of pathological proteins in ADRDs. In AD, their capacity to phagocytose Aβ is reduced, while in LBD, lysosomal dysfunction impairs the degradation of α-synuclein aggregates [142]. In FTD, specific tau protein isoforms, particularly hyperphosphorylated tau and aggregated tau species containing the 4R isoform (which predominates in many FTD variants), significantly disrupt microglial function through several mechanisms [143]. First, extracellular tau oligomers activate microglial toll-like receptors (particularly TLR2 and TLR4), triggering pro-inflammatory signaling cascades that shift microglia toward a dysfunctional phenotype with reduced phagocytic capacity [144]. Second, internalized tau impairs the microglial lysosomal function by disrupting acidification and cathepsin activity, compromising their ability to degrade protein aggregates [145]. Third, tau-activated microglia upregulate NLRP3 inflammasome activity, resulting in sustained IL-1β release that further promotes tau phosphorylation and aggregation in neurons, creating a detrimental feedback loop [144]. Additionally, tau pathology induces microglial senescence characterized by telomere shortening and accumulated DNA damage, leading to decreased expression of homeostatic genes and phagocytic receptors such as TREM2, CD33, and Cx3cr1 [146]. These molecular changes collectively impair the microglial clearance of pathological tau species and cellular debris, exacerbating tau propagation and neurotoxicity in FTD [147,148].

3.3. Microglial Transcriptional Alterations

Microglial transcriptional profiles across ADRDs reflect disease-specific and overlapping changes that drive their pathological activation [149,150]. Upregulation of genes associated with the NF-κB signaling pathway is a consistent feature, promoting the production of inflammatory cytokines (e.g., IL-1β) and activating inflammasome components such as NLRP3 [151,152] These transcriptional shifts contribute to chronic inflammation, oxidative stress, and impaired protein clearance mechanisms [152,153].

In FTD and LBD, microglia exhibit additional transcriptional changes, including the upregulation of genes involved in IL-6 signaling and metabolic dysfunction, further driving neuroinflammation and synaptic damage [133,154]. In VCID, ischemia-induced transcriptional reprogramming activates pathways linked to hypoxia and the AIM2 inflammasome, exacerbating neuronal injury and BBB disruption.

In AD, mutations in APP, PSEN1, and PSEN2 drive Aβ accumulation, triggering sustained microglial activation [155,156]. The ApoE ε4 allele amplifies these responses, promoting pro-inflammatory states and metabolic deficits [157]. FTD-associated mutations in MAPT and GRN impair tau clearance and enhance inflammatory signaling [157,158]. In LBD, GBA mutations disrupt lysosomal function, worsening α-synuclein aggregation and neuroinflammation [159,160]. In VCID and MEDs, APOE ε4 and C9orf72 mutations heighten microglial reactivity, accelerating the inflammatory and vascular components of pathology [161,162].

To summarize, microglia play a pivotal role in ADRDs, transitioning from protective to pathological states as the diseases progress. Their activation is marked by profound morphological changes, including hypertrophy, ramification, and process retraction, often leading to the adoption of a dystrophic morphology. Functionally, activated microglia release excessive pro-inflammatory cytokines (e.g., TNF-α, IL-1β, and IL-6) and chemokines (e.g., CCL2, CCL5, and CXCL10), creating a self-perpetuating inflammatory cycle that exacerbates neuronal damage and disrupts synaptic function. Additionally, microglial dysfunction impairs their capacity to clear pathological aggregates such as Aβ, tau, and α-synuclein, further amplifying neurotoxicity. Transcriptional reprogramming, driven by pathways such as NF-κB and influenced by genetic mutations (e.g., APP, GRN, GBA, and APOE ε4), compounds these effects by promoting chronic inflammation, oxidative stress, and metabolic disruption.

Our analysis of microglial contributions to ADRD pathogenesis reveals their central role in orchestrating neuroinflammatory responses and their potential to both protect against and exacerbate neurodegenerative processes (Figure 2, Table 2). As we have seen, the complex interactions between microglia and astrocytes create inflammatory feedback loops that significantly impact disease trajectory. However, this neuroimmune axis represents only part of the glial response to ADRDs. To fully understand the multicellular basis of neurodegeneration, we must also consider oligodendrocytes, which have received comparatively less attention in ADRD research despite growing evidence of their involvement.

Oligodendrocytes, the myelinating cells of the CNS, differ fundamentally from astrocytes and microglia in both origin and primary function. Derived from oligodendrocyte precursor cells (OPCs) that persist throughout adulthood, these cells are primarily responsible for producing and maintaining the myelin sheaths that insulate axons, enabling saltatory conduction and providing metabolic support to neurons [163]. Traditionally, oligodendrocyte dysfunction has been associated with demyelinating disorders such as multiple sclerosis rather than ADRDs. However, emerging evidence indicates significant oligodendrocyte and white matter abnormalities across the spectrum of neurodegenerative diseases [164]. The following section will examine how oligodendrocytes respond to and contribute to ADRD pathogenesis, their interactions with other glial populations, and how myelin dysfunction influences cognitive decline in these conditions. This analysis will complete our examination of individual glial cell types before we explore their collective interactions in driving neuroinflammation and neurodegeneration.

Table 2. Summary of the morphological changes, functional impairments, and transcriptional alterations of microglia in ADRDs.

	Morphological Changes	Functional Impairments	Transcriptional Alterations
All ADRDs	Hypertrophy [108,109] Increased ramification [108,109] Process retraction [108,109] Transition from homeostatic to reactive state [165,166]	Release of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) [128,167] Dysregulated chemokines (CCL2 and CCL5) [131,132] Oxidative stress from ROS [140,168] Impaired protein clearance [142,147,148]	NF-κB pathway upregulation [149,150] Genetic mutations amplify inflammation and dysfunction [152,153]
AD	Cluster around amyloid-β plaques [110,111] Dystrophic morphology (fragmented processes, rounded cell bodies) [112,113,114]	Impaired Aβ clearance [113] Chronic inflammation from persistent activation [113]	Dysregulated genes linked to Aβ phagocytosis [155,156] APP and PSEN1/2 mutations sustain activation [155,156]
FTD	Clustering surrounds tau pathology [116,117] Disorganized processes [169]	Exacerbates tau-mediated neurotoxicity [142] Impaired neuron interaction [142]	Upregulated tau-related inflammatory (IL-6) pathways [157,158] MAPT and GRN mutations impair function [157,158]
LBD	Hyper-ramification from α-synuclein aggregates [120] Synaptic support disruption [120]	Impaired α-synuclein degradation [148] Oxidative stress causes dopaminergic neuron loss [148]	Dysregulated genes linked to α-synuclein clearance [159] GBA mutations disrupt lysosomal function [160]
VCID	Chronic ischemia-induced loss of processes critical for maintaining neurovascular unit integrity [122,130]	Increased BBB permeability [122] Amplified neuronal vulnerability [130]	Hypoxia-induced transcriptional changes [161] AIM2 inflammasome activation [162]
MEDs	Amplified abnormalities [123,124] Widespread structural dysfunction [123,124]	Combined vascular and neurodegenerative damage [119,141] Severe BBB breakdown [141]	Overlapping AD and VCID transcriptional changes [133,154] APOE ε4 and C9orf72 mutations heighten reactivity [161,162]

Table 2. Summary of the morphological changes, functional impairments, and transcriptional alterations of microglia in ADRDs.

	Morphological Changes	Functional Impairments	Transcriptional Alterations
All ADRDs	Hypertrophy [108,109] Increased ramification [108,109] Process retraction [108,109] Transition from homeostatic to reactive state [165,166]	Release of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) [128,167] Dysregulated chemokines (CCL2 and CCL5) [131,132] Oxidative stress from ROS [140,168] Impaired protein clearance [142,147,148]	NF-κB pathway upregulation [149,150] Genetic mutations amplify inflammation and dysfunction [152,153]
AD	Cluster around amyloid-β plaques [110,111] Dystrophic morphology (fragmented processes, rounded cell bodies) [112,113,114]	Impaired Aβ clearance [113] Chronic inflammation from persistent activation [113]	Dysregulated genes linked to Aβ phagocytosis [155,156] APP and PSEN1/2 mutations sustain activation [155,156]
FTD	Clustering surrounds tau pathology [116,117] Disorganized processes [169]	Exacerbates tau-mediated neurotoxicity [142] Impaired neuron interaction [142]	Upregulated tau-related inflammatory (IL-6) pathways [157,158] MAPT and GRN mutations impair function [157,158]
LBD	Hyper-ramification from α-synuclein aggregates [120] Synaptic support disruption [120]	Impaired α-synuclein degradation [148] Oxidative stress causes dopaminergic neuron loss [148]	Dysregulated genes linked to α-synuclein clearance [159] GBA mutations disrupt lysosomal function [160]
VCID	Chronic ischemia-induced loss of processes critical for maintaining neurovascular unit integrity [122,130]	Increased BBB permeability [122] Amplified neuronal vulnerability [130]	Hypoxia-induced transcriptional changes [161] AIM2 inflammasome activation [162]
MEDs	Amplified abnormalities [123,124] Widespread structural dysfunction [123,124]	Combined vascular and neurodegenerative damage [119,141] Severe BBB breakdown [141]	Overlapping AD and VCID transcriptional changes [133,154] APOE ε4 and C9orf72 mutations heighten reactivity [161,162]

4. Oligodendrocytes

Oligodendrocytes, the myelinating cells of the central nervous system (CNS), play critical roles in supporting neuronal function by maintaining myelin integrity, providing metabolic support, and regulating extracellular ion balance [170,171]. In ADRDs, oligodendrocytes undergo pathological changes that disrupt these essential functions, contributing to neuroinflammation, demyelination, and neuronal injury [172]. Their involvement in ADRDs has emerged as a significant area of study, offering insights into their roles in disease pathogenesis [173].

4.1. Oligodendrocyte Morphological Changes

Oligodendrocytes in ADRDs exhibit distinct morphological changes indicative of their reactive state [174]. Across all dementia types, hypertrophy and increased ramification are commonly observed, reflecting an attempt to respond to pathological conditions [175]. In AD, oligodendrocytes exhibit swelling, process fragmentation, and reduced structural stability, often clustering near Aβ plaques [176]. This morphological disruption compromises their ability to maintain myelin integrity, contributing to neuronal vulnerability and exacerbating cognitive decline [177].

In FTD, oligodendrocytes exhibit fragmented and disorganized processes associated with tau protein accumulation [178,179]. These changes impair their capacity to support neuronal health and amplify tau-mediated neurotoxicity. Similarly, LBD oligodendrocytes display hypertrophy and process instability in response to α-synuclein aggregates, further contributing to demyelination and myelin degradation [180].

In VCID, chronic cerebral hypoperfusion induces reactive oligodendrocytes with hypertrophied and dysfunctional processes [178]. These cells lose their structural associations with blood vessels, exacerbating BBB breakdown and facilitating peripheral immune cell infiltration [181]. MEDs present compounded structural abnormalities, including extensive process fragmentation and severe demyelination, reflecting the dual burden of vascular and neurodegenerative insults [182].

4.2. Oligodendrocyte Functional Impairments

Reactive oligodendrocytes in ADRDs display significant functional impairments that disrupt their homeostatic roles and contribute to disease progression [183,184,185]. Across dementia types, oligodendrocytes release elevated levels of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6 [183,184]. These cytokines foster a neuroinflammatory environment, exacerbating neuronal damage and impairing synaptic integrity [186].

Dysregulated chemokine production is another hallmark of oligodendrocytic dysfunction. Elevated levels of CCL2 (MCP-1), CCL5 (RANTES), and CXCL10 (IP-10) are commonly observed in ADRDs, facilitating the recruitment of peripheral immune cells to the CNS [187,188]. This chemokine-mediated inflammation creates a self-perpetuating cycle, amplifying microglial and astrocytic reactivity [189].

Oligodendrocytes also fail to effectively repair myelin in ADRDs. The loss of myelin integrity increases neuronal susceptibility to oxidative stress and excitotoxicity, further impairing neural networks critical for cognitive function [190,191]. This failure is particularly pronounced in VCID, where ischemic damage exacerbates oligodendrocytic dysfunction and contributes to neuronal and vascular instability [192]. Mixed dementias further highlight the compounded effects of these deficits, with oligodendrocytes struggling to manage the dual demands of vascular and neurodegenerative stressors [193].

4.3. Oligodendrocyte Transcriptional Alterations

Oligodendrocytes in ADRDs undergo significant transcriptional reprogramming, driven by inflammatory, oxidative, and metabolic stress pathways [173,194]. Upregulation of NF-κB signaling is a consistent feature across dementia types, promoting the production of inflammatory cytokines such as IL-1β and IL-6, which exacerbate neuroinflammation and impair oligodendrocytic functions [171,195]. In AD, this is accompanied by the reduced expression of genes involved in lipid metabolism and Aβ clearance, further amplifying toxicity [196,197].

Similar patterns are observed in frontotemporal dementia, where IL-6 signaling and tau-related genes are upregulated, impairing myelin maintenance and promoting tau aggregation [177,198]. LBD oligodendrocytes show transcriptional shifts that reduce lysosomal function, hindering α-synuclein degradation and exacerbating inflammation [199]. In VCID, transcriptional changes reflect ischemia-induced activation of hypoxia-responsive genes and AIM2 inflammasome signaling, contributing to vascular and neuronal instability [200]. MEDs combine these transcriptional disruptions, with heightened inflammatory and metabolic stress pathways exacerbating oligodendrocytic dysfunction [201].

Genetic mutations further compound these transcriptional changes. In Alzheimer’s disease, mutations in APP, PSEN1, and PSEN2 drive Aβ accumulation and inflammatory activation, while ApoE ε4 amplifies metabolic deficits and reactivity [202]. FTD mutations in MAPT and GRN impair tau clearance and promote inflammatory signaling [203]. LBD-associated GBA mutations reduce lysosomal efficiency, worsening α-synuclein pathology [204]. APOE ε4 and C9orf72 mutations in VCID and mixed dementias exacerbate inflammatory activation and BBB disruption, linking genetic and transcriptional dysfunction across ADRDs [205].

As discussed, oligodendrocytes—critical for maintaining myelin integrity and providing both metabolic and structural support to neurons—undergo significant pathological changes in ADRDs (Figure 3, Table 3). Reactive oligodendrocytes present in ADRDs display hypertrophy, process fragmentation, and structural destabilization, contributing to demyelination, blood-brain barrier breakdown, and increased neuronal vulnerability. By releasing pro-inflammatory cytokines (e.g., TNF-α and IL-1β) and chemokines (e.g., CCL2 and CXCL10), they foster a neuroinflammatory environment that amplifies glial and neuronal dysfunction. Transcriptional disruptions, driven by NF-κB activation and disease-related mutations (e.g., APP, GRN and GBA), further exacerbate oxidative stress and impair critical homeostatic functions. Despite these detrimental changes, oligodendrocytes remain a compelling therapeutic target, with potential interventions focusing on reducing inflammation and restoring their capacity for myelin repair.

The preceding sections have individually characterized how astrocytes, microglia, and oligodendrocytes respond to and contribute to ADRD pathogenesis. Each glial cell type exhibits unique patterns of reactivity and dysfunction that reflect their distinct physiological roles within the CNS. Astrocytes show compromised homeostatic functions and adopt neurotoxic secretory profiles, microglia develop persistent pro-inflammatory activation states with impaired phagocytic capacity, and oligodendrocytes exhibit myelin abnormalities and metabolic dysfunction that compromise axonal integrity. While examining these cell-specific responses provides valuable insights, it presents an inherently compartmentalized view of glial contributions to neurodegeneration. In reality, the CNS represents a highly integrated cellular network where no glial cell functions in isolation. Astrocytes, microglia, and oligodendrocytes engage in continuous, multidirectional communication through direct contact, secreted factors, and extracellular vesicles [206]. These intercellular dialogues create complex signaling networks that collectively determine the neuroinflammatory environment and neuronal fate in ADRDs. The following section will explore these critical glial interactions, focusing on how communication between different glial populations amplifies or mitigates neurodegenerative processes. Understanding these cellular conversations is essential for developing therapeutic strategies that target not just individual cell types but the dysfunctional multicellular networks characteristic of ADRDs.

Table 3. Summary of the morphological changes, functional impairments, and transcriptional alterations of oligodendrocytes in ADRDs.

	Morphological Changes	Functional Impairments	Transcriptional Alterations
All ADRDs	Hypertrophy [175] Increased ramification [175] Process fragmentation [175] Reactive state disrupts structural stability [172,177]	Pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) [178,180] Dysregulated chemokines (e.g., CCL2 and CXCL10) [183,184] Impaired myelin repair and metabolic support [179,181,182]	NF-κB pathway upregulation [171,195] Genetic mutations exacerbate dysfunction [171,195]
AD	Swelling, process fragmentation [176,207] Cluster near amyloid-β plaques [176,207]	Compromised myelin integrity [176] Increased neuronal vulnerability, cognitive decline [207]	Reduced lipid metabolism and Aβ clearance genes [196,197] Amplified toxicity from APP and PSEN mutations [202] ApoE ε4 amplifies metabolic deficits [202]
FTD	Fragmented, disorganized processes [178,179] Associated with tau accumulation [178,179]	Amplified tau-mediated neurotoxicity [178,179] Impaired neuronal support [178,179]	Upregulated tau-related genes [203] IL-6 signaling drives inflammation [203]
LBD	Process instability [180] Response to α-synuclein aggregates [180]	Contributes to demyelination and myelin degradation [199] Promotes oxidative stress [199]	Reduced lysosomal function hinders α-synuclein clearance [199] GBA mutations worsen dysfunction [204]
VCID	Dysfunctional processes [178] Loss of structural association with blood vessels [182]	BBB breakdown exacerbates immune cell infiltration [192] Impaired neurovascular stability [192]	Hypoxia-responsive gene activation [201] AIM2 inflammasome signaling [200]
MEDs	Extensive process fragmentation [182] Severe demyelination from vascular and neurodegenerative insults [183]	Compounded structural and metabolic deficits [193] Heightened BBB disruption [193]	Overlapping AD and VCID transcriptional changes [171,195] Combined inflammatory and oxidative stress [171,195]

Table 3. Summary of the morphological changes, functional impairments, and transcriptional alterations of oligodendrocytes in ADRDs.

	Morphological Changes	Functional Impairments	Transcriptional Alterations
All ADRDs	Hypertrophy [175] Increased ramification [175] Process fragmentation [175] Reactive state disrupts structural stability [172,177]	Pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) [178,180] Dysregulated chemokines (e.g., CCL2 and CXCL10) [183,184] Impaired myelin repair and metabolic support [179,181,182]	NF-κB pathway upregulation [171,195] Genetic mutations exacerbate dysfunction [171,195]
AD	Swelling, process fragmentation [176,207] Cluster near amyloid-β plaques [176,207]	Compromised myelin integrity [176] Increased neuronal vulnerability, cognitive decline [207]	Reduced lipid metabolism and Aβ clearance genes [196,197] Amplified toxicity from APP and PSEN mutations [202] ApoE ε4 amplifies metabolic deficits [202]
FTD	Fragmented, disorganized processes [178,179] Associated with tau accumulation [178,179]	Amplified tau-mediated neurotoxicity [178,179] Impaired neuronal support [178,179]	Upregulated tau-related genes [203] IL-6 signaling drives inflammation [203]
LBD	Process instability [180] Response to α-synuclein aggregates [180]	Contributes to demyelination and myelin degradation [199] Promotes oxidative stress [199]	Reduced lysosomal function hinders α-synuclein clearance [199] GBA mutations worsen dysfunction [204]
VCID	Dysfunctional processes [178] Loss of structural association with blood vessels [182]	BBB breakdown exacerbates immune cell infiltration [192] Impaired neurovascular stability [192]	Hypoxia-responsive gene activation [201] AIM2 inflammasome signaling [200]
MEDs	Extensive process fragmentation [182] Severe demyelination from vascular and neurodegenerative insults [183]	Compounded structural and metabolic deficits [193] Heightened BBB disruption [193]	Overlapping AD and VCID transcriptional changes [171,195] Combined inflammatory and oxidative stress [171,195]

5. Interactions Among Glial Cells

In the pathogenesis and progression of ADRDs. These interactions are complex and involve many signaling pathways, inflammatory responses, and metabolic processes that can protect or harm neuronal health. In ADRDs, microglial activation plays a central role in initiating and sustaining neuroinflammation. As previously discussed, microglia release a variety of pro-inflammatory cytokines upon activation, such as IL-1α, TNF-α, and C1q, which propagate a neurotoxic environment. These cytokines induce a phenotypic transformation in astrocytes, inducing a reactive state. Reactive astrocytes are characterized by their neurotoxic properties, contributing to the death of neurons and oligodendrocytes. In the context of AD, the resultant neuroinflammation further exacerbates the accumulation of Aβ plaques, triggering the activation of additional microglia. The ensuing cascade initiates a chronic, low-grade inflammation that perpetuates neuronal degeneration and cognitive decline [208]. Microglial activation is not limited to cytokine release but also involves the secretion of extracellular vesicles that carry neurotoxic factors, further enhancing neuronal damage. These vesicles can contain a variety of harmful molecules, including inflammatory mediators and neurotoxic proteins, thus amplifying the inflammatory cascade, and contributing to the neurodegenerative process [209]. The interplay between microglia, astrocytes, and neurons underscores the complexity of neuroinflammation in AD, among other ADRDs, suggesting that targeting microglial activation and its downstream effects may provide potential therapeutic avenues for mitigating disease progression.

Astrocytes, traditionally viewed as supportive cells, play a dual role in ADRDs. While they are essential for maintaining homeostasis and supporting neuronal function, reactive astrocytes can adopt a neurotoxic phenotype under the influence of activated microglia. This phenotypic transformation is especially pronounced in AD, where reactive astrocytes not only exacerbate neuroinflammation but directly contribute to synaptic dysfunction and neuronal loss [210]. The interaction between astrocytes and microglia is integral to disease progression; activated microglia amplify the neurotoxic effects of astrocytes, thereby establishing a detrimental feedback loop that perpetuates neurodegeneration and cognitive decline [95,211]. Beyond their role in neuroinflammation, astrocytes are also critical for the regulation of oligodendrocyte survival and myelination, processes that are essential for the maintenance of neuronal function and overall CNS integrity [210]. Thus, while astrocytes are pivotal in the preservation of neuronal homeostasis, their dysregulation in ADRDs highlights their dual role as both protectors and contributors to neurodegeneration, further complicating the pathophysiology of these diseases.

Oligodendrocytes, the myelinating cells of the CNS, are significantly affected by the interactions between microglia and astrocytes. Under the inflammatory conditions stimulated by activated microglia and reactive astrocytes in ADRDs, oligodendrocytes become increasingly susceptible to apoptosis [212,213]. The loss of oligodendrocytes due to these inflammatory processes leads to demyelination, a critical event that disrupts neuronal conduction and contributes to the cognitive deficits observed in ADRDs [213]. In addition to mature oligodendrocytes, oligodendrocyte precursor cells (OPCs) are also affected by the inflammatory microenvironment shaped by microglia and astrocytes. Depending on the nature of these signals, OPCs can either be driven toward differentiation into mature oligodendrocytes or subjected to dysfunction, impairing their ability to regenerate and maintain myelin [214,215]. The balance between promoting OPC differentiation and preventing their dysfunction is crucial for preserving white matter integrity and overall brain health. Disruptions in this balance, particularly in the inflammatory environment of neurodegenerative diseases, exacerbate myelin loss and contribute significantly to the progressive cognitive decline seen in ADRDs.

As the primary functional units of the CNS, neurons are central to these interactive processes. Neurons not only communicate with glial cells but also influence their behavior through the release of signaling molecules. In ADRDs, neuronal dysfunction can lead to altered glial responses, creating a vicious cycle of neurodegeneration. For instance, in AD, the loss of synaptic integrity and neuronal death can further activate microglia and astrocytes, exacerbating the inflammatory response and promoting the progression of the disease [205]. Additionally, the metabolic interactions between neurons, astrocytes, and oligodendrocytes are critical for maintaining energy homeostasis in the brain, and disruptions in these interactions can lead to neuronal damage [215,216].

The interplay between these cell types is also influenced by various signaling pathways and molecular mechanisms. For example, the complement system, particularly the activation of complement component C1q, has been implicated in microglial-mediated synaptic pruning, which can be detrimental in neurodegenerative context [211]. Furthermore, microglia and astrocytes release extracellular vesicles carrying neurotoxic factors that affect neuronal health. This highlights the importance of intercellular communication in ADRD progression [209].

The interactions among glial cells and neurons manifest differently across specific ADRDs. In AD, the accumulation of amyloid plaques and tau tangles leads to a pronounced inflammatory response characterized by activated microglia and reactive astrocytes. These activated cells contribute to synaptic loss and neuronal death [208]. In FTD, the presence of tau pathology can similarly activate glial cells, resulting in neuroinflammation and neurodegeneration [217]. In LBD, the aggregation of alpha-synuclein in neurons can also provoke a neuroinflammatory response, with microglia and astrocytes playing significant roles in the disease’s progression [218]. VCID and MED present unique challenges as well, as they often involve vascular factors that can influence glial cell behavior. In VCID, ischemic events can lead to the activation of microglia and astrocytes, resulting in a cascade of inflammatory responses that can exacerbate neuronal injury [210,219]. The interplay between these cell types in the context of vascular pathology is critical, as it can determine the extent of neuronal damage and cognitive decline. Moreover, the role of oligodendrocytes in these diseases cannot be overlooked. In conditions such as multiple sclerosis, which shares features with VCID, oligodendrocyte loss and demyelination are key pathological features that can be influenced by the inflammatory milieu created by activated microglia and astrocytes [212,213]. The interactions among these cell types can significantly impact the regenerative capacity of the CNS, as oligodendrocyte dysfunction can hinder remyelination and recovery following injury [215,216].

The intricate interactions among glial cells play a pivotal role in the pathogenesis of age-related neurodegenerative diseases (ADRDs). These intercellular communications establish neuroinflammatory cascades that can either exacerbate or mitigate neurodegenerative processes, depending on their activation states [220]. This dynamic interplay is crucial for maintaining the neurovascular unit and overall brain health, yet its dysregulation can lead to detrimental outcomes, including increased microgliosis and the release of neurotoxic factors that perpetuate neuronal damage and cognitive decline. Understanding the mechanisms regulating these glial interactions requires examining the molecular control systems governing their phenotypes and activation states [221]. Among these regulatory mechanisms, non-coding RNAs have emerged as particularly important modulators of glial function. Non-coding RNAs, particularly microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), represent sophisticated molecular switches that fine-tune gene expression without being translated into proteins. These RNA species regulate numerous aspects of glial biology, from differentiation and morphological plasticity to inflammatory signaling and phagocytic capacity. In the context of ADRDs, specific patterns of ncRNA dysregulation are associated with pathological glial phenotypes, suggesting their potential involvement in disease mechanisms [222]. The following section will explore how non-coding RNAs influence glial cell morphology and function, their dysregulation in ADRDs, and their potential as both biomarkers and therapeutic targets. This examination will bridge our understanding of cellular interactions with the molecular mechanisms that control them, providing a more comprehensive picture of the complex regulatory networks underlying neuroinflammation and neurodegeneration.

6. Non-Coding RNAs in Glial Cell Ramification, Morphology, and Neuroinflammation

Non-coding RNAs (ncRNAs) represent a diverse class of RNA molecules that, despite lacking protein-coding potential, exert profound regulatory control over gene expression and cellular processes. Among the various ncRNAs, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) have garnered particular attention for their pivotal roles in the modulation of glial cell behavior, including their differentiation, morphological changes, and response to neuroinflammatory stimuli. As described in more detail below, both miRNAs and lncRNAs are regulators of gene expression, but miRNAs primarily function through post-transcriptional regulation, whereas lncRNAs have more diverse mechanisms that influence transcriptional regulation, chromatin remodeling, and protein-protein interactions [223].

These ncRNAs are synthesized in the nucleus from their respective genomic loci in glial cells and can be transported to the cytoplasm, where they can elicit a response (e.g., an immune response during injury or disease [222]. ncRNAs can also be secreted into the extracellular space via transport mechanisms, including via small-membrane vesicles called extracellular vesicles (EVs) [224]. These processes may also involve specialized RNA-binding proteins and intracellular vesicles to facilitate intercellular communication (described in more detail below). Once in the cytoplasm, ncRNAs can bind to target mRNAs, regulating gene expression either by repressing translation or promoting mRNA degradation [225].

miRNAs, such as miR-124 and miR-9, govern the balance between the homeostatic and reactive states of glial cells, impacting their structure and function in neurodegenerative conditions such as Alzheimer’s disease. Similarly, lncRNAs, including Bdnf-AS and NEAT1, regulate cytoskeletal dynamics and inflammatory pathways, further influencing glial cell activation and neuroinflammatory responses. Given their central roles in glial biology, these ncRNAs present promising therapeutic targets for neurodegenerative diseases, offering potential strategies to mitigate neuroinflammation and restore cellular homeostasis. The continued exploration of their mechanisms will be critical for developing ncRNA-based treatments for diseases such as Alzheimer’s.

6.1. miRNAs

miRNAs are classified based on their primary sequences and evolutionary conservation across species. Their nomenclature follows a system based on the sequence of their precursor stem-loop structures and their discovery as specific regulatory RNAs in the nervous system [226]. These miRNAs are approximately 22 nucleotides in length and regulate gene expression post-transcriptionally, typically resulting in the downregulation of target genes [227].

In the context of glial cells, miRNAs may elicit their responses as endogenous miRNAs, which are produced within the glial cells themselves, or exogenous miRNAs, which are secreted by other cells. Endogenous miRNAs can regulate glial cells’ internal processes, including differentiation, response to injury, and inflammation [228]. Exogenous RNAs, on the other hand, are secreted from cells, including neurons and other glial cells. They can be transferred to neighboring cells via the mechanisms described above. This form of intercellular communication allows miRNAs to influence the behavior of distant or neighboring glial cells, even across the blood–brain barrier in some cases. In this scenario, miRNAs secreted by neurons can affect glial cells, modulating their activity and potentially influencing synaptic function, neuroinflammation, or myelination [229].

Emerging evidence suggests that miRNAs are centrally involved in the regulation of astrocyte and microglial gene expression and function [96]. For example, miRNAs such as miRNA-124 and miRNA-9 are involved in regulating glial cell morphology, with alterations in this morphology linked to neuroinflammation and ADRDs [47,230,231]. For example, miRNA-9, which is expressed in all glial cells, can regulate neuroinflammation, neurogenesis, and neuronal differentiation [232]. miRNA-124 is also a brain-specific miRNA and is highly enriched in neurons, although it is also expressed in glial cells, particularly astrocytes [96]. One mechanism by which miR-124 may be involved in neuronal health and differentiation is through its regulation of the mTOR (mechanistic target of rapamycin) signaling pathway, which is crucial for cell growth, protein synthesis, and metabolism [233]. miRNA-9, on the other hand, has been implicated in the NF-κB pathway, a critical signaling pathway involved in inflammation and immune responses. miR-9 can target genes in the NF-κB pathway, modulating its activation and thus regulating neuroinflammation [234]. Given the roles of these miRNAs in acting on these proteins, evidence suggests that these miRNAs play an important role in neuronal differentiation, regulating neuroinflammation, synaptic plasticity, and glial cell differentiation. In addition to affecting cellular morphology, miRNAs may also directly modulate neuroinflammatory responses—an intrinsic feature of ADRDs—by influencing microglial activation states, transitioning from homeostatic to reactive phenotypes [235].

Homeostatic microglia exhibit a highly branched, neuroprotective morphology, which is associated with the release of anti-inflammatory cytokines [236]. In contrast, reactive microglia adopt an amoeboid, rounded morphology with shortened processes, accompanied by an enhanced capacity for phagocytosis and the production of pro-inflammatory cytokines [235]. Disruptions in miRNA expression are strongly associated with the induction of the reactive microglial phenotype, mediating morphological alterations through the activation of critical transcription factors and signaling pathways, including NF-κB, a central mediator of neuroinflammation [235]. Specific miRNAs, such as miRNA-146, miRNA-223, and miRNA-155, have been implicated in these processes, with links to changes in microglial morphology and activation, as well as astrogliosis and broader neuroinflammatory responses [237].

Another well-studied miRNA in the context of glial cell differentiation, morphology, and activation is miR-124. For instance, during the morphological transition of microglia from a ramified to an amoeboid state, several immune cell surface markers, including CD45 and major histocompatibility complexes (MHCs), are upregulated, coinciding with the downregulation of miR-124 [238]. Furthermore, the expression of both miR-124 and miR-9 has been implicated in the regulation of genes that govern cytoskeletal dynamics, which in turn contributes to the development of the characteristic star-shaped, branched morphology of astrocytes [96]. Additionally, miR-9 has been shown to modulate astrocyte morphology by influencing the extension and branching of processes through the regulation of actin- and tubulin-related genes [239]. Beyond these specific examples, miRNAs in general are broadly differentially expressed in AD and other dementias, driving alterations in glial morphology and promoting reactive phenotypes [240]. For example, the upregulation of miRNA-146a has been linked to reactive astrocytes—through synaptic dysfunction and impaired repair mechanisms—promoting neuroinflammation and neuronal damage [237]. Similarly, miR-223 and miR-155 have been associated with changes in astrocyte morphology, reactive astrogliosis, and downstream neurotoxicity [241,242]. However, the precise mechanisms by which other miRNAs contribute to disease pathogenesis remain incompletely understood, representing a critical area for future research.

The growing body of evidence highlighting the critical role of miRNAs in regulating glial cell function, morphology, and activation suggests their potential as therapeutic targets in ADRDs. In this context, both the use of miRNA inhibitors, which aim to mitigate the adverse effects of dysregulated miRNAs, and miRNA mimetics, designed to downregulate specific target genes, represent promising avenues of research. Strategies that modulate miRNA expression, such as targeting specific miRNAs with synthetic oligonucleotide inhibitors, have the potential to restore normal glial cell morphology and function, potentially preventing gliosis and neuroinflammation [243,244,245,246,247]. Additionally, the overexpression of artificial miRNAs is emerging as another promising strategy to improve glial health and counteract neurodegenerative processes [248,249,250].

6.2. lncRNAs

lncRNAs, typically >200 nucleotides in length, are also emerging as RNA regulators of glial cell ramification and morphology, influencing processes such as differentiation, synaptic interactions and neuroinflammation [251]. Growing evidence demonstrates that multiple lncRNAs can regulate the cytoskeleton, gene expression, and cellular signaling, thus shaping the structure and function of glial cells [252]. Much of this research suggests that lncRNAs contribute to glial changes by modulating cytoskeletal dynamics (including actin and tubulin levels), branching, and morphology (e.g., by binding with and interacting with actin filaments and microtubules) [253]. As such, they may also represent novel targets for therapeutic interventions in neurological disorders that involve glial cell dysfunction/reactivity, again in a bidirectional fashion. For example, increasing select lncRNAs has been reported to improve cognitive function and reduce glial cell inflammation [254], whereas decreasing other lncRNAs may reduce microglia-associated inflammation [255].

In addition to regulating cytoskeletal dynamics, lncRNAs have also been shown to interact with a variety of proteins that directly influence glial cytoskeletal dynamics. For example, the lncRNA brain-derived neurotrophic factor antisense (Bdnf-AS) can influence astrocyte morphology and branching by interacting with the mTOR signaling pathway, a key regulator of cytoskeletal dynamics (e.g., dendrite branching) [256]. Additional lncRNAs, including nuclear rich abundant transcript 1 (NEAT1) can modulate glial activation (reducing NEAT1 seems to be neuroprotective) in part by modulating transcriptional activity of NF-kB [257,258]. As described above, NEAT1 may also be involved in MTOR signaling, highlighting its role in neuron homeostasis and survival [259]. Another lncRNA, H19, can induce the activation of astrocytes, microglia, and the release of pro-inflammatory cytokines (interleukin-1β, interleukin-6, and tumor necrosis factor-α) [260].

In neurodegenerative diseases such as AD, which is characterized by heightened levels of neuroinflammation, glial cells undergo significant changes in morphology. As described above, lncRNAs can modulate glial cell activation, process extension, and the inflammatory response (e.g., by shifting microglia from an M2 state to an M1 activated state), which is associated with pathological progression [235]. Recent evidence suggests that lncRNAs can contribute to glial cell responses during pathological conditions, including neuroinflammation and reactive gliosis.

To summarize, the roles of miRNAs and lncRNAs in regulating glial cell morphology and function are pivotal in understanding neuroinflammatory processes and neurodegenerative diseases such as Alzheimer’s disease

Table 4. Summary of miRNAs and lncRNAs that regulate glial cell morphology and function in ADRDs.

	Effect on Glial Cells
miR-124	Regulates glial cell morphology, influencing astrocyte branching. Affects neuronal health and differentiation by regulating the mTOR pathway. Downregulated during the microglial transition to a reactive state, contributing to neuroinflammation.
miR-9	Modulates neuroinflammation by targeting genes in the NF-κB pathway. Affects neurogenesis, neuronal differentiation, and astrocyte morphology by regulating actin- and tubulin-related genes.
miR-146	Linked to reactive astrocytes, promoting neuroinflammation, impaired repair mechanisms, and neuronal damage.
miR-223	Associated with changes in astrocyte morphology and reactive astrogliosis, contributing to neurotoxicity and neuroinflammation.
miR-155	Implicated in neuroinflammation and changes in astrocyte morphology, contributing to reactive gliosis and neurotoxic responses.
miR-146a	Induces reactive microglia and promotes neuroinflammation, synaptic dysfunction, and neuronal damage.
Bdnf-AS	Modulates astrocyte morphology and branching by interacting with the mTOR signaling pathway.
NEAT1	Regulates glial activation and inflammation and interacts with the NF-κB pathway. Modulates glial response, including microglia transition from the M2 state to the M1 state. Decreasing NEAT1 is neuroprotective.
H19	Induces activation of astrocytes and microglia, promoting the release of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α).

. miRNAs, including miR-124 and miR-9, significantly influence the transition between the reactive and homeostatic states of microglia, thereby affecting neuroinflammation and neuronal health (Table 4). Concurrently, lncRNAs modulate cytoskeletal dynamics and inflammatory responses, further contributing to glial cell behavior during pathological conditions. The therapeutic potential of targeting these non-coding RNAs is promising, as restoring normal expression levels may mitigate neuroinflammation and promote glial health, highlighting the need for further research to elucidate their specific mechanisms and implications in neurodegenerative pathology.

7. Therapeutic Outlooks

In ADRDs, the complex interactions between glial cells are central to disease progression. These cells do not function in isolation; rather, they engage in dynamic interactions that regulate neuroinflammation, synaptic function, and neuronal health. Astrocytes provide metabolic support to neurons and modulate synaptic transmission, while microglia act as the primary immune cells of the CNS, responding to pathological changes by altering their activation states [261,262]. Oligodendrocytes, responsible for myelinating axons, also play a role in maintaining neuronal integrity and function. The intricate interplay among these glial populations, combined with their regulation by ncRNAs, presents a promising therapeutic target for mitigating the pathophysiological processes underlying ADRDs [263,264].

Therapeutic strategies that modulate the activation and function of glial cells, while also targeting ncRNAs, may restore the delicate balance required for proper neuroinflammatory responses and neuronal protection. For example, restoring astrocytic function through the inhibition of pro-inflammatory cytokines such as IL-1β and TNF-α, or by enhancing astrocytic glutamate uptake, could help mitigate the neurotoxic environment that promotes neurodegeneration [265,266].

Similarly, microglial activation is tightly regulated; strategies aimed at restoring their neuroprotective functions while dampening excessive pro-inflammatory activation show promise for slowing disease progression. Targeting chemokines, such as CCL2 and CXCL10, or modulating the activation of NF-κB and inflammasome signaling pathways, could prevent inflammatory escalation and restore glial homeostasis [267,268]. Moreover, the interactions between these glial cells and their ability to influence each other’s states further highlight the importance of a coordinated therapeutic approach. Enhancing astrocytic functions could, in turn, modulate microglial responses, offering a comprehensive strategy to restore the balance between pro-inflammatory and neuroprotective states in the brain [269,270].

ncRNAs, particularly miRNAs, have emerged as critical regulators of glial cell behavior and activation. miRNAs regulate key processes such as glial morphology, activation, and the inflammatory response. By modulating miRNA expression—through either miRNA inhibitors to prevent their adverse effects or mimetics to enhance their activity—it is possible to restore normal glial cell function. For instance, miRNAs such as miRNA-124 and miRNA-9, which influence the morphology of both astrocytes and microglia, could be targeted to promote protective glial phenotypes and counteract reactive transformations [271,272]. Additionally, modulating miRNAs involved in microglial activation could prevent neuroinflammation and mitigate neuronal damage. Targeting these pathways could be particularly effective in ADRDs, where dysregulated glial responses contribute to neuronal dysfunction and disease progression [273].

lncRNAs add another layer of complexity to glial regulation. Acting as competing endogenous RNAs (ceRNAs), lncRNAs can sequester miRNAs and modulate the expression of target mRNAs, many of which are involved in inflammatory processes [262,274]. Dysregulated lncRNA expression has been associated with increased neuroinflammation, and targeting these molecules could help restore glial homeostasis and reduce the pathological activation of glial cells. For example, lncRNAs such as NEAT1 have been implicated in the regulation of inflammatory responses in microglia, suggesting that their modulation could be beneficial in the context of ADRDs [121,275]. By modulating both miRNAs and lncRNAs, therapeutic strategies may be able to restore a balanced inflammatory response, mitigate neurodegeneration, and improve neuronal survival [276,277]. Several techniques might be used to inhibit ncRNAs, including antisense oligonucleotides, RNA interference (RNAi), and the development of other small molecules to target these RNAs [278]. The therapeutic potential of targeting glial cells and their interactions with ncRNAs offers a multifaceted approach to treating ADRDs. By addressing the dysregulation of both glial function and the molecular pathways that govern their activation, these strategies offer the potential to reprogram glial cells and halt or reverse the neurodegenerative processes that characterize ADRDs.

The temporal progression of glial activation and ncRNA dysregulation in ADRDs has significant implications for therapeutic development. Since these changes emerge in prodromal and early disease stages, they represent promising targets for early intervention before extensive neurodegeneration and cognitive decline occur [279]. Stage-specific therapeutic approaches that consider the evolving nature of glial phenotypes throughout disease progression may be particularly effective. For instance, interventions targeting microglial activation might be most beneficial in preclinical and early symptomatic phases, while treatments addressing oligodendrocyte dysfunction and myelin integrity might have a greater impact in later disease stages [280,281]. Similarly, ncRNA-based therapies may need to be tailored to the temporal expression patterns of specific ncRNAs throughout disease progression. This highlights the need for reliable biomarkers of glial activation and ncRNA dysregulation to identify appropriate therapeutic windows and monitor treatment efficacy in clinical trials [282].

Several challenges must be addressed in these therapeutic areas. For example, the blood–brain barrier (BBB) poses a challenge for delivering therapeutic agents (including miRNAs and lncRNAs) to the brain. Because the molecules are large and negatively charged, it is difficult to effectively target delivery in glial cells or neurons. Other challenges, including specificity and off-target effects, are also a concern. Various strategies, including lipid nanoparticles, exosomes, and viral vectors, are being explored to improve ncRNA delivery. Ongoing trials are focusing on these techniques, as well as the development of more efficient delivery systems [283]. As research into the role of glial cells and ncRNAs continues to evolve, the integration of ncRNA-based therapies with traditional cell-based approaches may provide a more comprehensive strategy to combat these complex diseases [284,285].

8. Concluding Remarks

The interplay between glial cells and non-coding RNAs (ncRNAs) is increasingly recognized as a critical factor in the pathogenesis and progression of ADRDs. Glial cells, including astrocytes, microglia, and oligodendrocytes, play essential roles in maintaining homeostasis within the central nervous system (CNS). However, their dysregulation can lead to neuroinflammation and neuronal dysfunction, contributing to the progression of neurodegenerative diseases. Recent studies have highlighted the dual nature of glial cells, where reactive changes can result in neurotoxic environments that exacerbate neuronal damage [285,286]. Furthermore, the identification of specific long non-coding RNAs (lncRNAs) that modulate glial cell behavior and fate determination has opened new avenues for understanding how these cells contribute to ADRDs [287].

ncRNAs, particularly lncRNAs and miRNAs, have emerged as significant regulators of gene expression and cellular responses in the context of neurodegeneration. These molecules are involved in various processes, including the modulation of inflammatory responses, regulation of glial cell function, and neuronal survival. For instance, lncRNAs have been shown to interact with transcription factors and other regulatory proteins, influencing the expression of genes associated with neuroinflammation and neurodegeneration [288,289]. Additionally, miRNAs can act as post-transcriptional regulators, fine-tuning the expression of genes involved in glial activation and neuronal health [290,291]. The complex regulatory networks involving glial cells and ncRNAs underscore the need for a comprehensive understanding of their roles in ADRDs.

Another important aspect of glial-mediated neuroinflammation in ADRDs involves the complement system, which serves as a critical bridge between glial reactivity and synaptic pathology. Reactive astrocytes and microglia upregulate the expression and secretion of various complement components, particularly C1q, C3, and C4, which tag vulnerable synapses for elimination [292]. For example, in AD, Aβ deposits activate the classical complement pathway, while in FTD, pathological tau induces similar complement activation [293]. Oligodendrocytes also contribute to this process by releasing complement factors in response to inflammatory stimuli [294]. This complement cascade creates a feed-forward mechanism where complement-mediated microglial phagocytosis of synapses drives network dysfunction before substantial neuronal loss occurs. Therapeutic strategies targeting this pathway, such as C1q or C3 inhibitors, have shown promise in preclinical models by preserving synaptic integrity while modulating glial reactivity [295]. Regarding ncRNA-based interventions, several innovative approaches are emerging. Beyond conventional antisense oligonucleotides (ASOs) targeting specific miRNAs, novel techniques include miRNA sponges that act as competitive inhibitors, CRISPR-Cas9-based approaches for modifying ncRNA expression, and small molecule inhibitors of ncRNA-protein interactions [296]. Extracellular vesicle-based delivery systems show particular promise for CNS targeting, as they can cross the blood-brain barrier and achieve cell-specific delivery [297]. Additionally, circular RNAs and aptamer-conjugated nanoparticles offer enhanced stability and specificity for ncRNA modulation in glial cells [298]. These complementary approaches—targeting both the complement system and ncRNA dysregulation—may provide synergistic benefits in restoring glial homeostasis and mitigating neuroinflammation in ADRDs [299].

Given the interplay between oligodendrocytes, astrocytes, and microglia, combinatory therapies addressing multiple glial dysfunctions may provide the most comprehensive approach to treating ADRDs [121]. Looking ahead, future research should focus on elucidating the specific mechanisms by which glial cells and ncRNAs interact. Advanced techniques such as single-cell RNA sequencing and spatial transcriptomics will be invaluable in mapping the expression profiles of glial cells and ncRNAs in both healthy and diseased states [300,301]. Understanding the temporal dynamics of these interactions will provide insights into how glial cells transition from protective to detrimental roles during the progression of neurodegenerative diseases. Moreover, the therapeutic potential of targeting glial cells and ncRNAs in ADRDs should be explored. For instance, modulating the expression of specific lncRNAs or miRNAs could restore normal glial function and mitigate neuroinflammation. Additionally, the development of ncRNA-based biomarkers for early diagnosis and the monitoring of disease progression could significantly enhance the clinical management of ADRDs [287]. As our understanding of the roles of glial cells and ncRNAs deepens, it may lead to innovative therapeutic strategies that target these pathways, improving outcomes for individuals affected by ADRDs.

In summary, the interaction between glial cells and non-coding RNAs represents a complex and dynamic regulatory network that plays a crucial role in the pathogenesis and progression of Alzheimer’s disease and related dementia. The dual roles of glial cells, coupled with the regulatory functions of ncRNAs, highlight the importance of these cellular and molecular players in maintaining CNS homeostasis and their potential contributions to neurodegeneration. As research continues to uncover the intricate mechanisms underlying these interactions, there is a promising opportunity to develop novel therapeutic strategies that target glial cells and ncRNAs. By advancing our understanding of these processes, we can pave the way for innovative approaches to prevent and treat ADRDs, enhancing the quality of life for affected individuals and their families.