{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T12:19:14Z","timestamp":1791980354617,"version":"4.4.0"},"reference-count":184,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T00:00:00Z","timestamp":1765497600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Astrocytes and microglia constitute nearly half of all central nervous system cells and are indispensable for its proper function. Both exhibit striking morphological and functional heterogeneity, adopting either neuroprotective (A2, M2) or proinflammatory (A1, M1) phenotypes in response to cytokines, pathogen-associated molecular patterns (PAMPs)\/damage-associated molecular patterns (DAMPs), toll-like receptor 4 (TLR4) activation, and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling. Crucially, many of these phenotypic transitions arise during the earliest stages of neurodegeneration, when glial dysfunction precedes overt neuronal loss and may act as a primary driver of disease onset. This review critically examines glial-centered hypotheses of neurodegeneration, with emphasis on their roles in early disease phases: (i) microglial polarization from an M2 neuroprotective state to an M1 proinflammatory state; (ii) NLRP3 inflammasome assembly via P2X purinergic receptor 7 (P2X7R)-mediated K+ efflux; (iii) a self-amplifying astrocyte\u2013microglia\u2013neuron inflammatory feedback loop; (iv) impaired microglial phagocytosis and extracellular-vesicle\u2013mediated propagation of \u03b2-amyloid (A\u03b2) and tau; (v) astrocytic scar formation driven by aquaporin-4 (AQP4), matrix metalloproteinase-9 (MMP-9), glial fibrillary acidic protein (GFAP)\/vimentin, connexins, and janus kinase\/signal transducer and activator of transcription 3 (JAK\/STAT3) signaling; (vi) cellular reprogramming of astrocytes and NG2 glia into functional neurons; and (vii) mitochondrial dysfunction in glia, including Dynamin-related protein 1\/Mitochondrial fission protein 1 (Drp1\/Fis1) fission imbalance and dysregulation of the sirtuin 1\/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Sirt1\/PGC-1\u03b1) axis. Promising therapeutic strategies target pattern-recognition receptors (TLR4, NLRP3\/caspase-1), cytokine modulators (interleukin-4 (IL-4), interleukin-10 (IL-10)), signaling cascades (JAK2\u2013STAT, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-\u03baB), phosphoinositide 3-kinase\u2013protein kinase B (PI3K\u2013AKT), adenosine monophosphate-activated protein kinase (AMPK)), microglial receptors (triggering receptor expressed on myeloid cells 2 (TREM2)\/spleen tyrosine kinase (SYK)\/ DNAX-activating protein 10 (DAP10), siglec-3 (CD33), chemokine C-X3-C motif ligand 1\/ CX3C motif chemokine receptor 1 (CX3CL1\/CX3CR1), Cluster of Differentiation 200\/ Cluster of Differentiation 200 receptor 1 (CD200\/CD200R), P2X7R), and mitochondrial biogenesis pathways, with a focus on normalizing glial phenotypes rather than simply suppressing pathology. Interventions that restore neuroglial homeostasis at the earliest stages of disease may hold the greatest potential to delay or prevent progression. Given the complexity of glial phenotypes and molecular isoform diversity, a comprehensive, multitargeted approach is essential for mitigating Alzheimer\u2019s disease and related neurodegenerative disorders. This review not only synthesizes pathogenesis but also highlights therapeutic opportunities, offering what we believe to be the first concise overview of the principal hypotheses implicating glial cells in neurodegeneration. Rather than focusing on isolated mechanisms, our goal is a holistic perspective\u2014integrating diverse glial processes to enable comparison across interconnected pathological conditions.<\/jats:p>","DOI":"10.3390\/ijms262411995","type":"journal-article","created":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T16:19:02Z","timestamp":1765556342000},"page":"11995","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Glial Cells in the Early Stages of Neurodegeneration: Pathogenesis and Therapeutic Targets"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0757-064X","authenticated-orcid":false,"given":"Eugenia","family":"Ahremenko","sequence":"first","affiliation":[{"name":"Faculty of Chemistry, Perm State University, 614068 Perm, Russia"},{"name":"Institute of Physics and Mathematics, Perm State University, 614068 Perm, Russia"},{"name":"Institute of Physiologically Active Compounds, Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, 142432 Chernogolovka, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Andreev","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, Perm State University, 614068 Perm, Russia"},{"name":"Institute of Physiologically Active Compounds, Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, 142432 Chernogolovka, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4459-5264","authenticated-orcid":false,"given":"Danila","family":"Apushkin","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, Perm State University, 614068 Perm, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5515-3387","authenticated-orcid":false,"given":"Eduard","family":"Korkotian","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, Perm State University, 614068 Perm, Russia"},{"name":"Department of Brain Sciences, The Weizmann Institute of Science, Rehovot 7610001, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3865","DOI":"10.1002\/cne.24040","article-title":"The Search for True Numbers of Neurons and Glial Cells in the Human Brain: A Review of 150 Years of Cell Counting","volume":"524","author":"Bahney","year":"2016","journal-title":"J. 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