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 production of (MMP-9).
Increased levels of cerebrospinal fluid MMP-9 were observed in human carriers of the AD-resilient variant rs1582763 near MS4A4A.
The findings suggest that loss of MS4A4A enhances Aβ clearance and reduces Alzheimer's disease pathology.
Simplified
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 (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 (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.
Key numbers
0.87 hours
Decrease in Aβ half-life
Aβ half-life in 5xFAD 4A-KO mice
2.7×
Increase in MMP-9 levels
MMP-9 levels in RAB-soluble fraction of 5xFAD 4A-KO mice
0.02
Reduction in plaque burden
Plaque burden quantification in the hippocampus of 5xFAD 4A-KO mice
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