Microglia-Mediated Synapse Loss in Alzheimer's Disease
Open accessAbstract
Microglia are emerging as key players in neurodegenerative diseases, such as Alzheimer's disease (AD). Thus far, microglia have rather been known as modulator of neurodegeneration with functions limited to neuroinflammation and release of neurotoxic molecules. However, several recent studies have demonstrated a direct role of microglia in “neuro” degeneration observed in AD by promoting phagocytosis of neuronal, in particular, synaptic structures. While some of the studies address the involvement of the β-amyloid peptides in the process, studies also indicate that this could occur independent of amyloid, further elevating the importance of microglia in AD. Here we review these recent studies and also speculate about the possible cellular mechanisms, and how they could be regulated by risk genes and sleep. Finally, we deliberate on possible avenues for targeting microglia-mediated synapse loss for therapy and prevention. Dual Perspectives Companion Paper:Alzheimer's Disease and Sleep-Wake Disturbances: Amyloid, Astrocytes, and Animal Models by William M. Vanderheyden, Miranda M. Lim, Erik S. Musiek, and Jason R. Gerstner
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Microglia-mediated synaptic pruning is a fundamental physiological process during development, but its proposed reactivation during ageing has deleterious consequences and may account for much of the memory loss and cognitive decline observed in AD.
“While microglia-mediated synaptic pruning is a fundamental physiological process during development, its proposed reactivation during ageing has deleterious consequences and may account for much of the memory loss and cognitive decline observed in AD [24].”
From Heterozygous expression of the Alzheimer’s disease-protective PLCγ2 P522R variant enhances Aβ clearance while preserving synapses (2022) · cites this paper as [24]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredThe microglial responses to plaques, tangles, and dying neurons are prominent in the human AD brain as well as in animal models, while aberrant microglial activity is associated with synaptic and neuronal loss.
“Further, the microglial responses to plaques, tangles, and dying neurons are prominent in the human AD brain as well as in animal models, while aberrant microglial activity is associated with synaptic and neuronal loss [96–98].”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [96]
The Introduction (page unavailable) documents microglia around amyloid plaques in humans and AD mouse models. The “Microglia-mediated synapse loss in AD” section (page unavailable) links dysfunctional or activated microglia to synapse loss. The passages do not establish prominent microglial responses to tangles or dying neurons, or an association with neuronal loss distinct from synapse loss. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAβ may facilitate synaptic pruning by microglia by acting as a tag for targeting synapses.
“It has been suggested that Aβ may facilitate synaptic pruning by microglia by acting as a tag for targeting synapses [24].”
From Heterozygous expression of the Alzheimer’s disease-protective PLCγ2 P522R variant enhances Aβ clearance while preserving synapses (2022) · cites this paper as [24]
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“While microglia-mediated synaptic pruning is a fundamental physiological process during development, its proposed reactivation during ageing has deleterious consequences and may account for much of the memory loss and cognitive decline observed in AD [24].”
Background
- Authors
- Rajendran, L., & Paolicelli, R. C.
- Affiliations
- University of Zurich (CH)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2018-03-21
- Volume
- 38
- Issue
- 12
- Pages
- 2911-2919
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6596066
- OpenAlex
- W2791832923
- Cited by
- 355
- References
- 30
- Citations by year
- 2026: 30 · 2025: 37 · 2024: 54 · 2023: 48 · 2022: 50 · 2021: 62 · 2020: 43 · 2019: 22 · 2018: 8 · 2017: 1
- FWCI
- 15.18
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- National Science Foundation
- Velux Stiftung
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Universität Zürich
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- microglia, synaptic loss, Alzheimer's disease, microglial phagocytosis, neuroinflammation, amyloid-beta, risk genes, sleep, neurodegeneration, therapeutic targeting
- MeSH terms
- Alzheimer Disease, Animals, Humans, Nerve Degeneration, Synapses, Microglia
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