Alzheimer's Disease Risk Variants Interact with Amyloid-beta to Modulate Monocyte Function

Area of Science:

• Immunology
• Neuroscience
• Genetics

Background:

• Genetics implicates innate immunity in Alzheimer's disease (AD), but peripheral myeloid cell roles, like monocytes, are understudied compared to microglia.
• Specific AD-associated genetic loci, CD33 (rs3865444) and SPI1 (rs1057233), are investigated for their functional impact on monocytes.

Purpose of the Study:

• To investigate if AD-associated loci in CD33 and SPI1 converge on shared functional pathways in monocytes.
• To examine the functional consequences of these variants in monocytes stimulated with amyloid-beta peptide 1-42 (Aβ1-42).

Main Methods:

• Isolation of monocytes from peripheral blood mononuclear cells (PBMCs) of healthy individuals.
• Exposure of isolated monocytes to aggregated Aβ1-42 to mimic an immune challenge.

Main Results:

• Functional convergence of CD33 and SPI1 AD risk variants was identified in monocytes exposed to aggregated Aβ.
• Both variants led to reduced phagocytic activity and decreased surface TREM2 expression in monocytes.
• These genetic and environmental interactions reduce myeloid cell fitness.

Conclusions:

• Peripheral monocytes, similar to microglia, are genetically and functionally linked to AD risk.
• These findings highlight the significance of monocytes as accessible immune cells contributing to AD susceptibility and progression.
• The study underscores the importance of considering peripheral immune cells in Alzheimer's disease research.