Year: 2025
Type: article
Abstract: BACKGROUND: Triggering receptor expressed on myeloid cells 2 (TREM2) is a gene specifically expressed in brain microglia, with genetic variants associated with increased Alzheimer's disease (AD) risk. In addition to its membrane-bound form, TREM2 is also released as a soluble form (sTREM2), which has been linked to improved cognitive outcomes in AD. Recent studies have identified MS4A4A as a key regulator of sTREM2; however, its precise role in regulating sTREM2 and its impact on AD pathology remain unclear. METHOD: To investigate this, we utilized the 5xFAD mouse model and overexpressed either wild-type MS4A4A or the AD-associated variant MS4A4A-M159V specifically in microglia. We measured TREM2 and sTREM2 levels, evaluated microglial survival, and examined the clustering of microglia around amyloid plaques. Additionally, we assessed amyloid-beta clearance, quantified amyloid burden, and evaluated cognitive function. RESULT: Overexpression of wild-type MS4A4A resulted in significantly increased TREM2 and sTREM2 levels, promoted microglial survival, facilitated microglial clustering around amyloid plaques, and enhanced Aβ clearance. These changes led to a reduction in amyloid burden and improved cognitive function. In contrast, the MS4A4A-M159V variant failed to produce these effects, and similar outcomes were observed in TREM2-deficient models. CONCLUSION: Our findings underscore the critical role of MS4A4A in modulating AD pathology through TREM2. These results position MS4A4A as a promising therapeutic target for AD.
Source: Alzheimer s & Dementia
Authors: Xiao‐Fen Chen, Hengjun Rao
Institution: Xiamen University
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,200
OpenAlex ID: W7117245107
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