biostudies-literatureDanhash EPNCATS NIH HHSEdward N. and Della L. Thome Memorial FoundationNIA NIH HHSNational Institutes of HealthHope Center for Neurological DisordersChan Zuckerberg InitiativeNIH HHSNational Institute on AgingWashington UniversityThe recruitment and clinical characterization of Knighte70580https://www.ebi.ac.uk/biostudies/studies/S-EPMC12371455biostudies-literatureUnknown21(8)<h4>Introduction</h4>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.<h4>Methods</h4>Using a novel model, we investigated the impact of Ms4a4a loss in the 5xFAD mouse model of amyloid beta (Aβ) accumulation.<h4>Results</h4>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 eAlzheimer's & dementia : the journal of the Alzheimer's AssociationMs4a4a deficiency ameliorates plaque pathology in a mouse model of amyloid accumulation.PMC12371455UL1 TR002345P30 AG066444P30AG066444P01 AG026276P01AG026276R01 AG062734RF1 AG058501P01AG03991AG058501AG062734P01 AG003991R01 AG058501Miller NNadarajah CJYou SFVerbeck ACHuang GStarr EIyer AKTiemann Powles SWestern DHerz JDanhash EPCruchaga CMusiek ESKarch CMDiaz-Pacheco ASGalasso GCirrito JfalseMs4a4a deficiency ameliorates plaque pathology in a mouse model of amyloid accumulation.<h4>Introduction</h4>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.<h4>Methods</h4>Using a novel model, we investigated the impact of Ms4a4a loss in the 5xFAD mouse model of amyloid beta (Aβ) accumulation.<h4>Results</h4>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 e2025-01-01T00:00:00Z2025 Aug2026-07-15T14:23:59.048Z2026-07-05T03:12:07.03ZS-EPMC123714554084377510.1002/alz.70580