Ms4a4a deficiency ameliorates plaque pathology in a mouse model of amyloid accumulation

Danhash, E. P.; Verbeck, A. C.; Western, D.; Diaz-Pacheco, A.; Galasso, G.; You, S.-F.; Nadarajah, C. J.; Tiemann-Powles, S.; Huang, G.; Musiek, E. S.; Herz, J.; Iyer, A. K.; Cirrito, J.; Cruchaga, C.; Karch, C. M.

doi:10.1101/2025.03.06.641917

bioRxiv · 10.1101/2025.03.06.641917

Ms4a4a deficiency ameliorates plaque pathology in a mouse model of amyloid accumulation

Danhash, E. P.·Verbeck, A. C.·Western, D.·Diaz-Pacheco, A.·Galasso, G.·You, S.-F.·Nadarajah, C. J.·Tiemann-Powles, S.·Huang, G.·Musiek, E. S.·Herz, J.·Iyer, A. K.·Cirrito, J.·Cruchaga, C.·Karch, C. M.

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Abstract

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. Using a mouse model of amyloid beta (A{beta}) accumulation (5xFAD), we examined the impact of Ms4a4a loss on A{beta} pathology. Before A{beta} accumulation, Ms4a4a loss reduces steady-state A{beta} levels and shortens A{beta} 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 A{beta} and A{beta} 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. Together, our results suggest that loss of Ms4a4a improves A{beta} pathology by altering A{beta} clearance, offering insights for therapeutic interventions in AD.

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Danhash, E. P., Verbeck, A. C., Western, D., Diaz-Pacheco, A., Galasso, G., You, S.-F., Nadarajah, C. J., Tiemann-Powles, S., Huang, G., Musiek, E. S., Herz, J., Iyer, A. K., Cirrito, J., Cruchaga, C., Karch, C. M.. 2025-03-10. Ms4a4a deficiency ameliorates plaque pathology in a mouse model of amyloid accumulation. https://doi.org/10.1101/2025.03.06.641917

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