Microglia in Brain Development, Homeostasis, and Neurodegeneration
Open accessAbstract
Advances in human genetics have implicated a growing number of genes in neurodegenerative diseases, providing insight into pathological processes. For Alzheimer disease in particular, genome-wide association studies and gene expression studies have emphasized the pathogenic contributions from microglial cells and motivated studies of microglial function/dysfunction. Here, we summarize recent genetic evidence for microglial involvement in neurodegenerative disease with a focus on Alzheimer disease, for which the evidence is most compelling. To provide context for these genetic discoveries, we discuss how microglia influence brain development and homeostasis, how microglial characteristics change in disease, and which microglial activities likely influence the course of neurodegeneration. In all, we aim to synthesize varied aspects of microglial biology and highlight microglia as possible targets for therapeutic interventions in neurodegenerative disease.
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Microglia constantly eliminate cell debris and dead cells through highly efficient phagocytosis.
“Microglia constantly eliminate cell debris and dead cells through highly efficient phagocytosis using specific recognition, engulfment, and degradation processes to maintain brain homeostasis in health and disease [310,325,326,327].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [327]
The “Microglial Clearance of Apoptotic Cells” section says microglia remove dead cells through phagocytosis and describes receptors involved in that process. The cited passages do not establish that they do so constantly or with the claimed high efficiency, and the passage mentioning cellular debris concerns complement-mediated clearance in the periphery. (LLM, conf=0.82)
Experimental — accuracy not yet measuredOnce abnormally reactive in Alzheimer's disease, microglia can promote synaptic and neuronal loss while exacerbating tau proteinopathy.
“Once abnormally reactive in AD, microglia can promote synaptic and neuronal loss while exacerbating tau proteinopathy11,12.”
From Somatic cancer variants enriched in Alzheimer’s disease microglia-like cells drive inflammatory and proliferative states (2026) · cites this paper as [12]
Genetic risk studies suggest that microglia not only respond to Alzheimer's disease but also modulate its course.
“Studies of genetic risk for sporadic AD have suggested that microglia not only respond to disease but modulate disease course13.”
From Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease (2020) · cites this paper as [13]
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Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets
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“6,11,13,15,16,44 Microglial and astrocytic activation has also been reported in aged rodent and human brains, 25–29 but how such activation depends on the spatial context remains unclear.”
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Self-citationMicroglia regulate sleep through calcium-dependent modulation of norepinephrine transmission
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TREM2 ectodomain and its soluble form in Alzheimer’s disease
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The Role of Cysteine Protease Cathepsins B, H, C, and X/Z in Neurodegenerative Diseases and Cancer
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m6A methylation: Critical roles in aging and neurological diseases
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TGF-β Signaling in Microglia: A Key Regulator of Development, Homeostasis and Reactivity
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GPR34 senses demyelination to promote neuroinflammation and pathologies
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Comparative Analysis of Multiple Neurodegenerative Diseases Based on Advanced Epigenetic Aging Brain
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Macrophages in Glioblastoma Development and Therapy: A Double-Edged Sword
Wu, M., Shi, Y. K., Zhu, L., Chen, L., Zhao, X., & Xu, C. S. (2022) · Life · doi:10.3390/life12081225 · Cited by 19 · see citing works
Shang, C., Su, Y., Ma, J., Li, Z., Wang, P., Ma, H., Song, J., & Zhang, Z. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1434568 · Cited by 18 · see citing works
Neuroimmunological effects of early life experiences
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Microglial ASD-related genes are involved in oligodendrocyte differentiation
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Inflammatory response in epilepsy is mediated by glial cell gap junction pathway (Review)
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Involvement of integrin αvβ3 in thyroid hormone-induced dendritogenesis
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Tau polarizes an aging transcriptional signature to excitatory neurons and glia
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- Authors
- Bohlen, C. J., Friedman, B. A., Dejanovic, B., & Sheng, M.
- Affiliations
- Genentech (US)
- Venue
- Annual Review of Genetics
- Publisher
- Annual Reviews
- Published
- 2019-12-03
- Volume
- 53
- Issue
- 1
- Pages
- 263-288
- ISSN
- 0066-4197 (ISSN-L)
- 1545-2948
- OpenAlex
- W2972808567
- Cited by
- 212
- References
- 165
- Citations by year
- 2026: 17 · 2025: 29 · 2024: 53 · 2023: 36 · 2022: 33 · 2021: 26 · 2020: 18
- FWCI
- 1.99
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Annual Review of Genetics (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- microglia, Alzheimer's disease, neurodegeneration, brain development, brain homeostasis, microglial dysfunction, genetic risk factors, genome-wide association study, therapeutic target
- MeSH terms
- Aging, Alzheimer Disease, Animals, Brain, Central Nervous System, Complement Pathway, Classical, Gene Expression Regulation, Homeostasis, Humans, Macrophages, Transforming Growth Factor beta, Microglia, Neurodegenerative Diseases, Genetic Predisposition to Disease, Plaque, Amyloid
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