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Microglial phagocytosis in Alzheimer disease
Guy C Brown1, Peter St George-Hyslop2,3, Rosa C Paolicelli4
1Department of Biochemistry, University of Cambridge, Cambridge, UK. gcb3@cam.ac.uk.
Abstract:
Accumulating evidence indicates that Alzheimer disease (AD) is caused by dysregulated microglial phagocytosis. The main risk factor for AD is age, and ageing reduces microglial phagocytosis of amyloid-β (Aβ) plaques, while increasing microglial phagocytosis of synapses and neurons. Most of the known genetic risk for AD can be linked to microglial phagocytosis, including ABCA1, ABI3, ACE, ADAM17, APOE, APP, BIN1, BLNK, CD2AP, CD33, CLU, CR1, CTSB, CTSH, EED, GRN, INPP5D, LILRB2, PICALM, PLCG2, PSEN1, PTK2B, SIGLEC11, SORL1, SPI1, TMEM106B and TREM2. Moreover, the only disease-modifying treatments for AD - anti-Aβ antibodies - work by increasing microglial phagocytosis of Aβ aggregates. Microglial phagocytosis of Aβ via TREM2, LRP1, CD33, TAM receptors and anti-Aβ antibodies appears to reduce AD pathology by pruning and compacting plaques, restricting subsequent tau pathology, whereas microglial phagocytosis of synapses and neurons seems detrimental in the later stages of AD, via complement, P2Y6 receptor and TREM2. However, the roles of microglial phagocytosis in AD are complex and multifaceted, and improved treatments are likely to require a deeper understanding of these roles.
Insights
Alzheimer disease (AD) involves altered microglial phagocytosis, impacting amyloid-β (Aβ) clearance and neuronal health with age. Understanding these complex roles is key for developing effective AD treatments.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Alzheimer disease (AD) pathogenesis is increasingly linked to microglial phagocytosis dysregulation.
- Ageing exacerbates AD risk by impairing microglial amyloid-β (Aβ) plaque clearance while promoting neuronal and synaptic engulfment.
Purpose of the Study:
- To elucidate the multifaceted roles of microglial phagocytosis in Alzheimer disease (AD).
- To highlight the genetic links between microglial phagocytosis and AD risk.
- To explore the therapeutic potential of modulating microglial phagocytosis in AD.
Main Methods:
- Review of accumulating evidence on microglial phagocytosis in AD.
- Analysis of genetic risk factors associated with microglial phagocytosis in AD.
- Evaluation of current disease-modifying treatments targeting microglial phagocytosis.
Main Results:
- Numerous AD genetic risk factors directly implicate microglial phagocytosis pathways.
- Anti-amyloid-β (Aβ) antibodies, a disease-modifying AD treatment, enhance microglial Aβ phagocytosis.
- Microglial phagocytosis of Aβ appears beneficial by reducing plaques and tau pathology, while synaptic phagocytosis may be detrimental in later AD stages.
Conclusions:
- Microglial phagocytosis plays a complex, dual role in Alzheimer disease (AD) progression.
- Targeting microglial phagocytosis pathways offers potential for novel AD therapeutics.
- Further research into the intricate mechanisms of microglial phagocytosis is crucial for advancing AD treatment strategies.
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