Search Results (194)

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) and the accumulation of tau in the brain, which triggers robust innate immune responses. Growing evidence indicates that neuroinflammation contributes to AD progression by overactivating microglia through the release of cytokines and chemokines. In general, chemokines can disrupt neuronal communication and promote blood–brain barrier permeability. Peripheral immune cells are mobilized into the brain by a gradient of chemokines. These processes link peripheral immune responses with substantial T-cell infiltration into the CNS parenchyma, leptomeninges and cerebrospinal fluid of both AD mice and AD patients. This finding underscores the relevance of the adaptive immune system, particularly T and B cells, in AD neuropathology. T-cell infiltration into the brain can influence amyloid clearance through chemokine signalling. However, chemokines play a critical role in AD by either promoting or suppressing disease progression. The infiltration of peripheral T and B cells into the brain parenchyma can exacerbate neuronal loss, yet it may also exert neuroprotective effects. Despite the presence of CD4⁺ and CD8⁺ T cells in postmortem brains of AD patients, debate continues about their role in AD brains, in terms of whether they are protective or detrimental. Understanding the complex role of chemokines in controlling innate and adaptive immune responses by modulating neuron–glia interactions (involving astrocytes and microglia) may provide novel therapeutic approaches for AD. Targeting chemokine signalling or treating with drugs that can prevent the recruitment of immune cells may be promising strategies for treating AD neuropathology. Therapies that prevent the overactivation of T cells in the brain could lead to protective strategies against AD. In fact, regulatory T cells (Tregs) could delay the onset of cognitive symptoms, because they suppress inflammation and slow the accumulation of Aβ plaques and p-Tau in the brain. Complementary strategies, such as photobiomodulation, nanoparticle, and T-cell-based approaches, could mitigate AD progression in patients. Full article

Background/Objectives: Alzheimer’s disease (AD) is characterized by beta-amyloid (Aβ) plaque deposition, which impairs several cellular processes, including autophagy. Considering the multifactorial nature of AD, the development of therapies acting on alternative molecular targets is necessary. In this study, we evaluated the neuroprotective effect of a molecule from the hydrozoan Eudendrium carneum and investigated its impact on autophagy-related pathways. Methods: The secretion of E. carneum was fractionated by RP-HPLC according to its neuroprotective activity in SH-SY5Y cells exposed to oAβ42, evaluated using LDH and MTT assays. The purified molecule (named EC5), characterized by mass spectrometry, was evaluated regarding in silico toxicity and calcium dynamics. Neuronal lysosomal morphology was assessed using the LysoTracker probe, and cathepsin D activity was determined using a synthetic substrate. The expression of autophagy-related proteins (mTOR, LAMP-1, and LC3B) was evaluated by dot blotting, and amyloid plaque clearance was quantified using Thioflavin-T staining. Results: The steroid glycoside putatively identified as Sarmentoside B (EC5) exhibited neuroprotective effects and showed no toxicity or alterations in neuronal calcium or sodium channel dynamics. EC5 restored lysosomal morphology and cathepsin D activity, reversing the impairment induced by oAβ42. Furthermore, EC5 reduced mTOR expression, and this interaction was supported by molecular docking analysis. Lysosomal restoration promoted the clearance of oAβ42 aggregates, as evidenced by Thioflavin-T staining, resulting in reduced neuronal death. Conclusions: EC5, putatively identified as Sarmentoside B, exerts neuroprotective effects against oAβ42-induced toxicity by promoting autophagy-related amyloid clearance, highlighting its therapeutic potential for AD. Full article

Alzheimer’s disease (AD) is undergoing a profound paradigm shift, transitioning from a localized, monolithic proteinopathy into a complex, multisystem disorder. This critical review synthesizes recent mechanistic, translational, and clinical insights to dismantle the traditional linear amyloid cascade hypothesis. We explore the synergistic interplay between amyloid-β (Aβ) and tau propagation, positioning chronic neuroinflammation, endolysosomal failure, and metabolic starvation—often framed as “Type 3 Diabetes”—as fundamental disease drivers. Crucially, we highlight the emerging biological bridge of CNS-PNS crosstalk, where central neurodegeneration and peripheral neuropathies are linked by systemic immune activation and microbiota–gut–brain axis dysbiosis. The recent validation of disease-modifying therapies (DMTs) confirms Aβ clearance as a viable pharmacological target; however, the marginal clinical gains and severe radiological risks, such as Amyloid-Related Imaging Abnormalities (ARIA), expose the profound limitations of monotherapy. Ultimately, we argue that isolated amyloid clearance is merely an induction phase. The future of AD therapeutics mandates a sequential combination approach—pairing early plaque debulking with lifelong metabolic and neuroimmune maintenance. Supported by scalable fluid biomarkers (e.g., plasma p-tau217) and the expanded ATN(I) framework, the field must embrace proactive precision medicine and inclusive clinical trial designs to successfully transform AD into a manageable chronic condition. Full article

Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β (Aβ) and chronic neuroinflammation, with microglia playing a central role in its pathogenesis. Alterations in microglial metabolism have been proposed to contribute to AD-related inflammatory responses and reduced Aβ clearance, suggesting that thiamine-dependent pathways may be relevant in this context. Thiamine pyrophosphate (TPP), the active form of vitamin B1, is essential for glucose metabolism and mitochondrial function; however, its association with microglial changes in AD remains unclear. In this study, 9-month-old female triple-transgenic AD (3xTg-AD) mice and non-transgenic controls (NoTg) received TPP (2.0 mg/mL) or saline as a vehicle for six weeks via osmotic pumps. Nesting, a hippocampus-dependent behavioral test, as well analyses of Aβ burden, microglial morphology, and the expression of genes related to metabolic and immune pathways were evaluated. Differences in nesting behavior between experimental groups were observed, but TPP treatment was not associated with an evident change in 3xTg-AD mice. In the subiculum and CA1 regions of the hippocampus of female 3xTg-AD mice exposed to TPP, a lower Aβ burden was observed, and morphological variations in microglia were detected in both groups (3xTg-AD and NoTg). Additionally, in the brain of the TPP-treated group, some changes in mRNA gene expression were recorded. Together, these findings describe hippocampal microglial and amyloid profiles following TPP treatment in 3xTg-AD mice and provide a basis for further investigation of thiamine-dependent pathways in AD-related neuroinflammatory contexts. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) plaque deposition, neurofibrillary tau tangles, synaptic dysfunction, and progressive cognitive decline. AD is increasingly recognized as a condition in which chronic neuroinflammation actively shifts amyloid precursor protein (APP) processing toward the amyloidogenic pathway, driving Aβ production and accumulation rather than merely accompanying amyloid deposition. In this review, we examine the molecular cross-talk between inflammatory signalling and secretase regulation, highlighting how pro-inflammatory mediators promote amyloidogenic processing and contribute to downstream synaptic dysfunction. We discuss the major pathways linking glial activation to aberrant APP cleavage, including STAT3-dependent BACE1 upregulation, immune-mediated modulation of γ-secretase through IFITM3, and activation of the C/EBPβ/δ-secretase axis, which connects inflammatory stress to both amyloid and tau pathology. We further address the contribution of epigenetic mechanisms, particularly microRNA-mediated derepression of BACE1 and suppression of ADAM10, as well as SIRT3-related impairment of Aβ clearance. These interconnected processes establish a feed-forward pathogenic network in which neuroinflammation amplifies secretase imbalance, amyloidogenesis, and synaptic vulnerability. Finally, we discuss emerging multi-target therapeutic strategies aimed at modulating inflammatory signalling, restoring non-amyloidogenic APP processing, and preserving proteostatic and synaptic resilience. Collectively, this framework supports the view that targeting the inflammatory control of secretase activity may represent a biologically relevant strategy for disease modification in AD. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder classically defined by cerebral amyloid β (Aβ) plaque deposition and tau pathology. In recent years, AD has increasingly been recognized as a multisystem disorder rather than a purely brain-restricted condition, as mounting evidence indicates that Aβ metabolism is a dynamic, bidirectional process involving both central and peripheral compartments. Peripheral tissues, particularly platelets, liver, kidneys, and the gastrointestinal tract, contribute substantially to circulating Aβ levels and influence cerebral amyloid burden. Platelets are now considered the predominant source of peripheral Aβ, accounting for the majority of plasma Aβ under physiological and pathological conditions, while the liver and kidneys play critical roles in Aβ clearance through receptor-mediated uptake, enzymatic degradation and excretion. Disruption of these peripheral clearance pathways elevates circulating Aβ, increasing its transport into the brain via blood–brain barrier (BBB) mechanisms by enhanced RAGE-mediated influx and impaired LRP1-dependent efflux in AD. Peripheral Aβ entry into the central nervous system exacerbates neuroinflammation, mitochondrial dysfunction, and oxidative stress, thereby accelerating neuronal damage and disease progression. This review synthesizes updated evidence on peripheral sources of Aβ, differences between central and peripheral Aβ pools, mechanisms of Aβ transport across the BBB, pathological consequences of peripheral Aβ on the brain and emerging therapeutic strategies targeting peripheral Aβ metabolism, highlighting the importance of a systemic perspective in AD pathogenesis and treatment. Full article

Alzheimer’s disease (AD) remains an incurable neurodegenerative disorder. The concept of theranostics—combining diagnostic and therapeutic functions within a single nanoplatform—has been explored for over a decade. Despite a growing number of publications, no theranostic system has yet reached clinical application for AD. This critical review analyzes the fundamental conceptual contradictions that hinder the clinical translation of theranostic nanoplatforms for AD and identifies alternative strategies where nanotechnology may still be beneficial. The review presents key aspects essential for understanding theranostics challenges: AD molecular targets, analysis of existing nanoplatforms, identification of three inherent conceptual conflicts, and viable alternative approaches. Our analysis reveals three core conceptual conflicts: the pharmacokinetic conflict, where diagnostics demand rapid accumulation and clearance while therapy requires prolonged retention—exacerbated by minimal brain delivery (1–2% ID/g) and peripheral toxicity risks; the dose conflict, characterized by orders-of-magnitude disparities between diagnostic and therapeutic dosing, rarely quantified for identical particles; and the temporal conflict, pitting one-time diagnostics against chronic therapy needs, as long-persisting particles generate irremovable brain background signals. We further identify a pervasive methodological trap: predominant focus on mature β-amyloid (Aβ) fibrils overlooks soluble oligomers as the primary toxic species. We conclude by proposing viable alternatives: preclinical intervention for time-limited “hit-and-clear” applications; coordinated theranostic monitoring with separate diagnostics/therapy; theranostic pairs using ligand-matched, function-optimized particles; and external stimuli for temporal function separation. A practical roadmap guides the transition from conceptual demonstrations to clinical translation. Addressing these contradictions can transform theranostics from elegant chemical constructs into clinically meaningful AD tools. Full article

Type 2 Diabetes (T2D) is characterized by the toxic aggregation of human islet amyloid polypeptide (hIAPP or amylin) within pancreatic β-cells. IAPP is also a neuropancreatic hormone that plays a significant role in Alzheimer’s disease (AD) by co-depositing with amyloid-beta (Aβ) and Tau, supporting the Type 3 Diabetes (T3D) hypothesis. Soluble IAPP accelerates Aβ aggregation through cross-seeding and causes neurotoxicity by impairing the blood–brain barrier and activating neuroinflammation. Melatonin inhibits these processes by disrupting hydrophobic interactions in both hIAPP and Aβ, preventing the formation of toxic β-sheet structures. Furthermore, melatonin promotes amyloid clearance via the glymphatic and lymphatic systems, protects neurons from oxidative damage, and reduces Tau hyperphosphorylation. This suggests that melatonin serves as a promising multitarget therapeutic agent for both metabolic and neurodegenerative disorders by modulating structural protein transformations. Full article

Canine cognitive dysfunction (CCD) is a common age-related neurodegenerative disorder in dogs that shares several pathological and clinical features with human Alzheimer’s disease (AD). In both species, β-amyloid (Aβ) accumulates within the brain parenchyma and cerebral vessel walls and is associated with synaptic loss, oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation, ultimately leading to progressive cognitive decline. Increasing evidence indicates that impairment of brain clearance mechanisms, particularly the glymphatic system, represents a central pathogenic mechanism in both CCD and AD. The glymphatic system is a glia-dependent perivascular network involved in the clearance of Aβ and other metabolic waste products from the brain. Its function declines with aging, vascular disease, and astrocytic alterations, including changes in aquaporin-4 distribution. Reduced glymphatic and periarterial drainage promotes the retention and aggregation of Aβ and tau proteins. Compared with AD, tau pathology in CCD is generally less extensive, supporting the interpretation of CCD as an Aβ-predominant condition and a partial pathological analog of Alzheimer’s disease. Clinically, CCD is characterized by a constellation of behavioral changes including, disorientation, altered social interactions, sleep–wake cycle disturbances, a loss of housetraining, changes in activity levels, and increased anxiety, commonly summarized by the DISHAA acronym. Overall, CCD represents a valuable spontaneous large-animal model for investigating neurodegenerative mechanisms and clearance-related therapeutic targets relevant to both veterinary and human medicine. Full article

Pharmacological activation of brain Retinoid X Receptors (RXRs) enhances cognition and facilitates amyloid-beta (Aβ) clearance in Alzheimer’s disease (AD) mouse models, partly by upregulating apolipoprotein E (Apoe), a major AD genetic risk factor. However, the specific cellular contributions to these effects are unclear. Here, we used single-cell transcriptomic profiling to investigate cell subpopulation-specific responses to bexarotene, an RXR agonist, in APP/PS1 mice. Our analysis revealed that bexarotene activated cholesterol biosynthesis and lipid metabolism transcriptional programs in homeostatic astrocytes and oligodendrocytes. Astrocytes also upregulated neurodevelopmental genes, while oligodendrocytes and endothelial cells showed enhanced protein folding and cellular growth pathways. Bexarotene further modulated immune responses, promoting Aβ-responsive signatures in disease-associated microglia and reactive astrocytes while dampening pro-inflammatory responses in homeostatic microglia and endothelial cells. Furthermore, Apoe expression was significantly elevated across multiple cell types, especially in microglia and oligodendrocytes. Cell–cell communication analysis highlighted increased astrocyte-centered signaling, with APOE-driven pathways emerging as a prominent mediator. These findings clarify the molecular complexity of RXR-mediated regulation, revealing the cellular origins of bexarotene’s known effects as well as novel, cell-type-specific responses. This study provides mechanistic insights into RXR-targeted interventions and supports APOE-associated pathways as promising therapeutic targets in AD. Full article

Alzheimer’s disease (AD) is a serious medical challenge, representing an incurable and insidious disease. Current treatments can slow AD progression but cannot cure it. Promising new methods for AD therapy are essential for addressing the growing number of people with dementia, especially after the COVID-19 pandemic. The review highlights pioneering approaches to AD treatment based on innovative methods for the stimulation of brain drainage and clearance, in which the meningeal lymphatic vessels (MLVs) play a key role. Clinically promising noninvasive technologies using photobiomodulation for the effective clearance of metabolites, including amyloid beta (Aβ), and for the improvement of cognitive impairment during AD progression are discussed. An interesting part of the review is its analysis of innovative methods of improving the efficacy of anti-Aβ immunotherapy by stimulating MLV growth. The review is also focused on lifestyle, including sleep and physical exercises, discussing their support for the efficient lymphatic removal of waste products from the brain. Overall, the review provides an important, informative platform to excite the interest of a wide range of readers in the development of promising and clinically significant strategies for the treatment of AD, based on new strategies for the stimulation of brain drainage and clearance. Full article

The clinical safety of intravenous immunoglobulin (IVIG) is well-established, offering potential as a “one-drug, multi-target” intervention for Alzheimer’s disease (AD). However, its efficacy remains inconclusive and appears closely related to specific functional properties. Therefore, we conducted a systematic review based on the analysis of prior animal and clinical trials to provide insights for future IVIG-based therapeutic development. A systematic search was conducted across PubMed, Embase, the Cochrane Library, Web of Science, PsycInfo, ClinicalTrials.gov, SinoMed, and Wanfang databases for the relevant literature published up to 30 October 2025, using terms related to Alzheimer’s, IVIG, and β-amyloid protein. Consequently, IVIG demonstrated clinical safety, though methodologies—including dosages, models, and manufacturers—varied significantly across studies. In most cases, IVIG treatment delayed cognitive degradation in both AD mice and patients. Biologically, Aβ and tau levels increased in plasma while decreasing in the brain or cerebrospinal fluid (CSF), suggesting a peripheral clearance mechanism distinct from that of monoclonal antibody interventions. Additionally, brain atrophy was alleviated, and pathological plaques were reduced. In the context of plasma exchange (PE) combination therapy, the administration of IVIG further contributed to improvements in language, memory, and praxis. IVIG possesses a favorable safety profile and can ameliorate AD symptoms, yet efficacy varies considerably between trials. To advance treatment, future research should investigate the reasons for these variances and establish a standardized system for evaluating preclinical IVIG interventions, thereby facilitating the development of specific IVIG products for AD. Full article

Neuroimmune interactions play a critical role in the pathogenesis of neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), with microglia acting as key mediators of neuroinflammation. Microglia exhibit dual roles, contributing to both neuroprotection and neurotoxicity depending on their activation state. In AD, amyloid-beta (Aβ) aggregation leads to chronic microglial activation, resulting in excessive pro-inflammatory cytokine release (e.g., TNF-α, IL-1β, IL-6), oxidative stress, and synaptic dysfunction. In PD, α-synuclein aggregation triggers a similar neuroinflammatory cascade, exacerbating dopaminergic neuronal loss in the substantia nigra. Beyond inflammatory responses, microglia regulate synaptic plasticity, phagocytose pathological proteins, and interact with peripheral immune cells, influencing disease progression. Emerging evidence suggests that genetic variants in genes such as TREM2, CD33, and HLA modulate microglial function, thereby altering susceptibility to neurodegeneration. Dysregulated microglial responses, characterized by impaired clearance of protein aggregates and prolonged neuroinflammation, further amplify neuronal damage. Therapeutic strategies targeting microglial activation are under investigation, aiming to balance neuroinflammatory responses and enhance clearance mechanisms. Small-molecule inhibitors, monoclonal antibodies, and modulators of innate immune pathways are being explored to mitigate microglia-driven pathology. Understanding the complex interplay between microglia and neurodegeneration could pave the way for precision medicine approaches, optimizing treatments based on individual immune profiles. Further research is essential to delineate microglial heterogeneity across disease stages and uncover novel targets for therapeutic intervention. Full article

In both Alzheimer’s disease (AD) patients and animal models, senile plaques are generally observed in the cerebral cortex rather than the cerebellum. The mechanisms underlying the regional resistance of the cerebellum to amyloid plaque deposition remain poorly understood. We investigated this cerebellar resistance using 5xFAD mice, an amyloidosis model with high expression of mutant human APP and PSEN1 in the cortex and cerebellum. In aged 5xFAD mice, the cerebellum had minimal amyloid-β (Aβ) deposition despite robust transgene expression, correlating with lower expression levels of IBA1, CD68, TREM2, and CD36 (although elevated expression of CD45 and MHC I) compared to the cortex. Consistent with the absence of plaques, cerebellar tissue lacked the dystrophic VGLUT1-positive synaptic accumulations prominent in the cortex. Cerebellar microglia maintained a distinct, less inflammatory phenotype yet displayed efficient clearance activity. Notably, ASC inflammasome specks—capable of seeding Aβ aggregation—were paradoxically more abundant in the cerebellum, implying that rapid Aβ clearance prevents these seeds from driving plaque formation. Furthermore, key extracellular matrix (ECM) proteoglycans brevican and aggrecan were elevated in the 5xFAD cerebellum. Cerebellar microglia showed enhanced internalization of brevican alongside small Aβ aggregates, exceeding that in cortical microglia. These findings indicate that region-specific microglial and ECM interactions—particularly efficient uptake and degradation of ECM–Aβ co-aggregates—may underlie the cerebellum’s resilience to amyloid plaque pathology. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by decreased amyloid-beta (Aβ) clearance, enhanced Aβ aggregation, an increased risk of amyloid-related imaging abnormalities (ARIA), and blood–brain barrier (BBB) dysfunction. The APOE4 allele, being the leading genetic risk factor for AD, contributes strongly to these symptoms. This review covers the relationship between APOE4 status and the efficacy of FDA-approved monoclonal antibody (mAb) therapies, namely aducanumab, lecanemab, and donanemab. Across several clinical trials, APOE4 carriers exhibited higher rates of ARIA-E and ARIA-H compared to non-carriers. While the therapies did often meet biomarker endpoints (i.e., reduced amyloid), benefits were only observed in early and mild AD, and cognitive benefits were often marginal. Going forward, experimental apoE4-targeted immunotherapies may ease the burden of APOE4-related pathology. The field is shifting towards a more integrated approach, focusing on earlier interventions, biomarker-driven precision treatment, and improved drug delivery systems, such as subcutaneous injections, receptor-mediated transport, and antibodies with enhanced BBB penetration. As it stands, high treatment costs, limited accessibility, and strict eligibility criteria all stand as barriers to treatment. By integrating the APOE4 genotype into treatment planning and focusing on disease-stage-specific approaches, a safer and more effective means of treating AD could be achieved. Full article