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Microglia in Alzheimer's Disease: a Key Player in the Transition Between Homeostasis and Pathogenesis
Open accessAbstract
Immune activation accompanies the development of proteinopathy in the brains of Alzheimer's dementia patients. Evolving from the long-held viewpoint that immune activation triggers the pathological trajectory in Alzheimer's disease, there is accumulating evidence now that microglial activation is neither pro-amyloidogenic nor just a simple reactive process to the proteinopathy. Preclinical studies highlight an interesting aspect of immunity, i.e., spurring immune system activity may be beneficial under certain circumstances. Indeed, a dynamic evolving relationship between different activation states of the immune system and its neuronal neighbors is thought to regulate overall brain organ health in both healthy aging and progression of Alzheimer's dementia. A new premise evolving from genome, transcriptome, and proteome data is that there might be at least two major phases of immune activation that accompany the pathological trajectory in Alzheimer's disease. Though activation on a chronic scale will certainly lead to neurodegeneration, this emerging knowledge of a potential beneficial aspect of immune activation allows us to form holistic insights into when, where, and how much immune system activity would need to be tuned to impact the Alzheimer's neurodegenerative cascade. Even with the trove of recently emerging -omics data from patients and preclinical models, how microglial phenotypes are functionally related to the transition of a healthy aging brain towards progressive degenerative state remains unknown. A deeper understanding of the synergism between microglial functional states and brain organ health could help us discover newer interventions and therapies that enable us to address the current paucity of disease-modifying therapies in Alzheimer's disease.
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“Reviews and experimental studies now increasingly describe Alzheimer’s neuroinflammation as a dynamic balance between protective and harmful microglial programs, with disease stage and local tissue environment determining whether immune activation is beneficial, insufficient, maladaptive, or toxic [13,19].”
From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [13]
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“Microglia may help contain amyloid plaques, phagocytose pathological material, support synapses, and limit inflammatory spread; yet they may also release pro-inflammatory mediators, promote complement-associated synapse loss, propagate neurotoxic signaling, and contribute to chronic tissue damage.”
From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [13]
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“more recent work suggests that microglial responses in Alzheimer’s disease are not uniformly harmful and cannot be reduced to a simple activated-versus-resting distinction [13,14].”
From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [13]
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“The central unresolved issue is that the same broad category of “microglial activation” can describe processes with opposite biological consequences.”
From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [13]
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Cited by
Sorted by citations
Qin, J., Ma, Z., Chen, X., & Shu, S. (2023) · Frontiers in Neurology · doi:10.3389/fneur.2023.1103416 · Cited by 243
Khan, A. A., Mahendran, R. K., Perumal, K., & Faheem, M. (2024) · IEEE Transactions on Neural Systems and Rehabilitation Engineering · doi:10.1109/tnsre.2024.3357723 · Cited by 119
Therapeutic Potential of Allicin and Aged Garlic Extract in Alzheimer’s Disease
Tedeschi, P., Nigro, M., Travagli, A., Catani, M., Cavazzini, A., Merighi, S., & Gessi, S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23136950 · Cited by 61
Dysfunctional microglia and tau pathology in Alzheimer’s disease
Ayyubova, G. (2022) · Reviews in the Neurosciences · doi:10.1515/revneuro-2022-0087 · Cited by 36
New Insights into Microglial Mechanisms of Memory Impairment in Alzheimer’s Disease
Li, N., Deng, M., Hu, G., Li, N., Yuan, H., & Zhou, Y. (2022) · Biomolecules · doi:10.3390/biom12111722 · Cited by 30
Metadata
- Authors
- McFarland, K. N., & Chakrabarty, P.
- Affiliations
- University of Florida (US)
- Corresponding author
- Chakrabarty, Paramita
- Venue
- Neurotherapeutics
- Publisher
- Elsevier BV
- Published
- 2022-01
- Volume
- 19
- Issue
- 1
- Pages
- 186-208
- ISSN
- 1878-7479 (ISSN-L)
- PMC
- PMC9130399
- OpenAlex
- W4221004276
- Cited by
- 48
- References
- 265
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 15 · 2023: 10 · 2022: 7
- FWCI
- 1.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neurotherapeutics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- national institutes of health (P30AG066506, RF1AG064914)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- microglia, Alzheimer's disease, microglial activation, neuroinflammation, amyloid-beta, neurodegeneration, healthy aging, microglial phenotype, disease-modifying therapy
- MeSH terms
- Alzheimer Disease, Brain, Homeostasis, Humans, Neurons, Microglia
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