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Cells
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Aging and Neurodegeneration: Molecular Insights and Emerging Strategies
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Aging and Neurodegeneration: Molecular Insights and Emerging Strategies

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Aging".

Deadline for manuscript submissions: 30 August 2026 | Viewed by 8390

Editor

Dr. Piotr Paweł Chmielewski

E-Mail Website1 Website2
Guest Editor
Division of Anatomy, Faculty of Medicine, Wroclaw Medical University, Wrocław, Poland
Interests: biogerontology; biomarkers; geroprotective strategies; inflammation; longevity; molecular mechanisms of neurodegeneration; neuroinflammation; therapeutic interventions

Special Issue Information

Dear Colleagues,

The World Health Organization predicts that by 2050, the number of adults affected by dementia will exceed 150 million globally. This growing prevalence underscores the urgent need for a deeper understanding of the molecular and cellular processes driving neurodegenerative conditions to inform the development of effective therapeutic interventions. Age is the primary risk factor for many neurodegenerative disorders, including Alzheimer’s disease, other dementias, and Parkinson’s disease. These conditions are associated with mechanisms such as impaired mitophagy, oxidative stress, molecular damage, endolysosomal dysfunction, chronic inflammation, and altered intercellular communication mediated by extracellular vesicles. These disruptions contribute to hallmark pathologies, including protein misfolding and aggregation (e.g., amyloid-beta peptide, tau protein, or alpha-synuclein), synaptic dysfunction, and ultimately neuronal loss. While these mechanisms are often studied in isolation, a growing body of evidence reveals that they are interconnected. Understanding these pathways provides opportunities to identify common molecular targets for the development of novel therapeutic strategies. In this Special Issue, we invite contributions that explore the fundamental molecular pathways underlying age-related neurodegeneration, innovative biomarkers for early diagnosis, and novel therapeutic approaches. Submissions focusing on translational research, which is indispensable for bridging the gap between bench and bedside, integrative strategies, and systematic reviews are particularly encouraged.

Dr. Piotr Paweł Chmielewski
Guest Editor

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Keywords

  • Alzheimer’s disease
  • biomarkers
  • endolysosomal pathway
  • extracellular vesicles
  • inflammation
  • mitophagy
  • neurodegeneration
  • neuroinflammation
  • Parkinson’s disease
  • translational research

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Published Papers (4 papers)

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Research

Jump to: Review

22 pages, 4363 KB  
Article
Porphyromonas gingivalis-Lipopolysaccharide Induced Caspase-4 Dependent Noncanonical Inflammasome Activation Drives Alzheimer’s Disease Pathologies
by Ambika Verma, Gohar Azhar, Pankaj Patyal, Xiaomin Zhang and Jeanne Y. Wei
Cells 2025, 14(11), 804; https://doi.org/10.3390/cells14110804 - 30 May 2025
Cited by 11 | Viewed by 3918
Abstract
Chronic periodontitis, driven by the keystone pathogen Porphyromonas gingivalis, has been increasingly associated with Alzheimer’s disease (AD) and AD-related dementias (ADRDs). However, the mechanisms through which P. gingivalis-lipopolysaccharide (LPS)-induced release of neuroinflammatory proteins contribute to the pathogenesis of AD and ADRD [...] Read more.
Chronic periodontitis, driven by the keystone pathogen Porphyromonas gingivalis, has been increasingly associated with Alzheimer’s disease (AD) and AD-related dementias (ADRDs). However, the mechanisms through which P. gingivalis-lipopolysaccharide (LPS)-induced release of neuroinflammatory proteins contribute to the pathogenesis of AD and ADRD remain inadequately understood. Caspase-4, a critical mediator of neuroinflammation, plays a pivotal role in these processes following exposure to P. gingivalis-LPS. In this study, we investigated the mechanistic role of caspase-4 in P. gingivalis-LPS-induced IL-1β production, neuroinflammation, oxidative stress, and mitochondrial alterations in human neuronal and microglial cell lines. Silencing of caspase-4 significantly attenuated IL-1β secretion by inhibiting the activation of the caspase-4-NLRP3-caspase-1-gasdermin D inflammasome pathway, confirming its role in neuroinflammation. Moreover, caspase-4 silencing reduced the activation of amyloid precursor protein and presenilin-1, as well as the secretion of amyloid-β peptides, suggesting a role for caspase-4 in amyloidogenesis. Caspase-4 inhibition also restored the expression of key neuroinflammatory markers, such as total tau, VEGF, TGF, and IL-6, highlighting its central role in regulating neuroinflammatory processes. Furthermore, caspase-4 modulated oxidative stress by regulating reactive oxygen species production and reducing oxidative stress markers like inducible nitric oxide synthase and 4-hydroxynonenal. Additionally, caspase-4 influenced mitochondrial membrane potential, mitochondrial biogenesis, fission, fusion, mitochondrial respiration, and ATP production, all of which were impaired by P. gingivalis-LPS but restored with caspase-4 inhibition. These findings provide novel insights into the role of caspase-4 in P. gingivalis-LPS-induced neuroinflammation, oxidative stress, and mitochondrial dysfunction, demonstrating caspase-4 as a potential therapeutic target for neurodegenerative conditions associated with AD and related dementias. Full article
(This article belongs to the Special Issue Aging and Neurodegeneration: Molecular Insights and Emerging Strategies)
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Review

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24 pages, 1425 KB  
Review
Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis?
by James Chmiel, Wiktor Gawełczyk, Julia Soczyńska and Jerzy Leszek
Cells 2026, 15(13), 1151; https://doi.org/10.3390/cells15131151 - 24 Jun 2026
Viewed by 498
Abstract
Microglia are central regulators of Alzheimer’s disease pathogenesis, but their roles cannot be reduced to a simple protective-versus-harmful dichotomy. Genetic, single-cell, and spatial studies have shown that Alzheimer ’s-associated microglia occupy diverse disease-linked states shaped by amyloid plaques, tau pathology, lipid stress, complement [...] Read more.
Microglia are central regulators of Alzheimer’s disease pathogenesis, but their roles cannot be reduced to a simple protective-versus-harmful dichotomy. Genetic, single-cell, and spatial studies have shown that Alzheimer ’s-associated microglia occupy diverse disease-linked states shaped by amyloid plaques, tau pathology, lipid stress, complement activation, astrocyte signaling, aging, and immune genetic risk. Among the regulatory nodes controlling these states, SPI1, which encodes the myeloid transcription factor PU.1, has emerged as a key determinant of microglial identity and disease responsiveness. Human genetic studies suggest that reduced SPI1 expression may be protective, whereas experimental data indicate that excessive PU.1 suppression can impair essential microglial functions. This review examines the emerging concept that partial, plaque-associated reduction in PU.1 may enable a distinct lymphoid-like immunoregulatory microglial program marked by CD28 expression. Recent evidence suggests that PU.1-low CD28-positive microglia may restrain neuroinflammation and amyloid pathology, raising the possibility that Alzheimer’s plaques induce not only inflammatory and phagocytic microglial responses, but also endogenous suppressive programs that limit tissue damage. We discuss this proposed PU.1/CD28 regulatory axis in relation to disease-associated microglia, TREM2–APOE signaling, complement-mediated synapse loss, antigen-presentation pathways, plaque-niche biology, and therapeutic microglial reprogramming. We also highlight major unresolved questions, including whether PU.1-low CD28-positive microglia are present and functional in human Alzheimer’s disease, whether they are specific to amyloid-rich niches or extend to tau and mixed pathologies, and how such states could be safely manipulated without disrupting essential immune surveillance. We propose that lymphoid-like suppressive microglia represent a promising but still unproven framework for understanding protective neuroimmune regulation in Alzheimer’s disease and for developing state-specific microglial therapies. Full article
(This article belongs to the Special Issue Aging and Neurodegeneration: Molecular Insights and Emerging Strategies)
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23 pages, 852 KB  
Review
Emerging Function of Prolactin-Inducible Protein—Is This Important Tear Protein Found in Alzheimer’s Disease?
by James Chmiel, Wiktor Gawełczyk, Julia Soczyńska and Jerzy Leszek
Cells 2026, 15(11), 1029; https://doi.org/10.3390/cells15111029 - 3 Jun 2026
Viewed by 438
Abstract
Alzheimer’s disease is characterized by a chronic, long-term neurodegenerative process and an increasing need for easily accessible biomarkers that enable early diagnosis and disease monitoring. For this reason, tears have attracted growing interest as a potential source of such biomarkers, and prolactin-inducible protein [...] Read more.
Alzheimer’s disease is characterized by a chronic, long-term neurodegenerative process and an increasing need for easily accessible biomarkers that enable early diagnosis and disease monitoring. For this reason, tears have attracted growing interest as a potential source of such biomarkers, and prolactin-inducible protein is a candidate tear protein of mechanistic interest whose clinical value remains to be established as a biomarker of Alzheimer’s disease. The literature indicates that prolactin-inducible protein is physiologically present in the lacrimal apparatus. Proteomic studies in patients with Alzheimer’s disease have repeatedly demonstrated decreased levels of prolactin-inducible protein in tears, typically accompanied by reduced concentrations of other proteins associated with normal lacrimal gland function. Although the evidence remains inconclusive, these findings suggest that alterations in prolactin-inducible protein levels may reflect lacrimal gland dysfunction related to neurodegenerative processes, autonomic dysregulation, and inflammation. Nevertheless, the lack of specificity of prolactin-inducible protein for Alzheimer’s disease, as well as the influence of various factors on its concentration, limit its value as a standalone biomarker. The most plausible approach is the incorporation of prolactin-inducible protein into multimarker panels, which could enable improved patient stratification and assessment of lacrimal gland dysfunction in Alzheimer’s disease. Full article
(This article belongs to the Special Issue Aging and Neurodegeneration: Molecular Insights and Emerging Strategies)
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17 pages, 939 KB  
Review
Orthobiologics and Peptide Therapy for Central Nervous System Repair in Neurodegenerative Conditions
by Cézar Augusto Alves de Oliveira, Bernardo Scaldini Oliveira, Amanda Scaldini Oliveira, Rafael Duarte de Souza Loduca, Carlos Roberto Massella Junior and Gabriel Silva Santos
Cells 2025, 14(23), 1853; https://doi.org/10.3390/cells14231853 - 25 Nov 2025
Cited by 2 | Viewed by 2825
Abstract
Alzheimer’s disease and Parkinson’s disease remain the most prevalent neurodegenerative disorders associated with aging and continue to lack curative treatments. Their pathophysiology is often multifaceted, encompassing protein aggregation, mitochondrial dysfunction, chronic neuroinflammation, synaptic degeneration, and vascular compromise. This complex landscape reduces the effectiveness [...] Read more.
Alzheimer’s disease and Parkinson’s disease remain the most prevalent neurodegenerative disorders associated with aging and continue to lack curative treatments. Their pathophysiology is often multifaceted, encompassing protein aggregation, mitochondrial dysfunction, chronic neuroinflammation, synaptic degeneration, and vascular compromise. This complex landscape reduces the effectiveness of single-target pharmacological agents and underscores the need for therapies capable of acting across multiple axes. Orthobiologics and peptide-based strategies exemplify this approach. Autologous cellular alternatives such as platelet-rich plasma, bone marrow aspirates, mesenchymal stromal cell derivatives, and extracellular vesicles deliver paracrine signals that can reprogram glia, preserve mitochondrial function, and promote synaptic and vascular repair. Peptide therapeutics, including glucagon-like peptide-1 receptor agonists and novel sequences targeting protein aggregation or mitochondrial pathways, provide complementary precision by engaging defined receptors and intracellular cascades. Together, these modalities converge on mechanisms central to circuit preservation rather than symptomatic relief alone. Preclinical studies across Alzheimer’s and Parkinson’s disease demonstrate consistent neuroprotective and functional benefits, and early human trials support feasibility and safety. The translational path forward requires standardized preparation, biomarker integration, optimized delivery routes such as intranasal administration, and regulatory frameworks adapted to biologic therapies. This review synthesizes current evidence on orthobiologics and peptides in neurodegeneration, outlines safety and translational considerations, and highlights future directions, including rational combinations and biomarker-driven trials. By uniting the broad signaling capacity of orthobiologics with the precision of peptides, neurology can move beyond symptomatic care toward regenerative strategies that aim to preserve neural circuits and improve long-term outcomes in Alzheimer’s disease and Parkinson’s disease. Full article
(This article belongs to the Special Issue Aging and Neurodegeneration: Molecular Insights and Emerging Strategies)
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