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

INTRODUCTION

Genome-wide association studies have identified MS4A4A, a microglia-enriched gene, as a modulator of Alzheimer's disease (AD) risk. Common variants in MS4A4A affect AD susceptibility, gene expression, triggering receptor expressed on myeloid cells 2 (TREM2) signaling, and microglial transcriptional states, but the gene's functional role remains unclear.

METHODS

Using a novel model, we investigated the impact of Ms4a4a loss in the 5xFAD mouse model of amyloid beta (Aβ) accumulation.

RESULTS

Ms4a4a deficiency reduced steady-state Aβ levels and shortened its half-life in brain interstitial fluid. Aged 5xFAD mice lacking Ms4a4a exhibited more compact plaques and lower overall plaque burden. Microglia deficient in Ms4a4a showed a pro-inflammatory profile and elevated matrix metalloproteinase 9 (MMP-9) production, which may facilitate Aβ degradation. Notably, human carriers of the AD-resilient variant rs1582763 near MS4A4A also displayed increased cerebrospinal fluid MMP-9 levels.

DISCUSSION

Together, we show that Ms4a4a loss enhances Aβ clearance and reduces pathology, suggesting a protective mechanism that may inform microglia-targeted AD therapies.

HIGHLIGHTS

We examined the impact of Ms4a4a loss on amyloid beta (Aβ) pathology using a mouse model of Aβ accumulation (5xFAD). Ms4a4a loss reduces overall plaque burden and increases plaque compaction. Microglia lacking Ms4a4a are more pro-inflammatory and produce more matrix metalloproteinase 9 (MMP-9). Alzheimer's disease (AD) resilience variant carriers, MS4A4A rs1582763, exhibit significantly elevated levels of cerebrospinal fluid MMP-9. Our findings suggest that reduction of MS4A4A may be a therapeutic approach for AD.