Ms4a4a deficiency ameliorates plaque pa thology in a mouse model of amyloid accumulation
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Background
Genome-wide association studies for Alzheimer disease (AD) risk have identified a number of genes enriched in microglia, including MS4A4A . Common variants in MS4A4A influence AD risk, MS4A4A expression, TREM2 signaling, and a specific microglial transcriptional state, though the exact role of MS4A4A in AD remains unclear.
Methods
Using a mouse model of amyloid beta (Aβ) accumulation (5xFAD), we examined the impact of Ms4a4a loss on Aβ pathology.
Results
Before Aβ accumulation, Ms4a4a loss reduces steady-state Aβ levels and shortens Aβ half-life in brain interstitial fluid. In aged 5xFAD Ms4a4a- deficient mice, plaques are more compact with reduced overall plaque burden. Microglia lacking Ms4a4a are more pro-inflammatory and produce more MMP-9, which may promote degradation of Aβ and Aβ fibrils. Human subjects that carry a variant near MS4A4A (rs1582763) that confers resilience to AD also exhibit significantly elevated levels of MMP-9 in their cerebrospinal fluid.
Conclusions
Together, our results suggest that loss of Ms4a4a improves Aβ pathology by altering Aβ clearance, offering insights for therapeutic interventions in AD.
