ArticleAlzheimer's & dementia : the journal of the Alzheimer's Association2025
Ms4a4a deficiency ameliorates plaque pathology in a mouse model of amyloid accumulation.
Article in Alzheimer's & dementia : the journal of the Alzheimer's Association, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Article
- Spatial characterisation of TREM2 expression in actively demyelinating multiple sclerosis lesions supports its key roles in lipid metabolic pathways.Acta neuropathologica communications · 2026Article
- Ms4a4a deficiency ameliorates plaque pathology in a mouse model of amyloid accumulation.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- MALT1 in cerebrospinal fluid: a prognostic biomarker and potential therapeutic target in Alzheimer's disease.Frontiers in neurology · 2025Article
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17 authors.
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Abstract
introductionGenome-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.
methodsUsing a novel model, we investigated the impact of Ms4a4a loss in the 5xFAD mouse model of amyloid beta (Aβ) accumulation.
resultsMs4a4a 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.
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