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Published on: June 14, 2020
Basic Science and Pathogenesis
Xiao-Fen Chen1,2, Hengjun Rao1
1Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, Fujian, China.
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.
Insights
MS4A4A enhances Alzheimer's disease (AD) pathology by increasing soluble TREM2 (sTREM2) levels, promoting microglial function, and improving cognition. The MS4A4A-M159V variant lacks these beneficial effects, highlighting MS4A4A as a potential therapeutic target for AD.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Triggering receptor expressed on myeloid cells 2 (TREM2) genetic variants increase Alzheimer's disease (AD) risk.
- Soluble TREM2 (sTREM2) is linked to improved cognitive outcomes in AD.
- MS4A4A is identified as a regulator of sTREM2, but its role in AD is unclear.
Purpose of the Study:
- Investigate the role of MS4A4A in modulating AD pathology via TREM2.
- Determine the impact of wild-type and variant MS4A4A on microglial function and AD hallmarks.
Main Methods:
- Utilized 5xFAD mouse model with microglial overexpression of wild-type or variant MS4A4A.
- Measured TREM2 and sTREM2 levels, microglial survival, and clustering around amyloid plaques.
- Assessed amyloid-beta clearance, amyloid burden, and cognitive function.
Main Results:
- Wild-type MS4A4A increased TREM2/sTREM2, promoted microglial survival and clustering, and enhanced amyloid-beta clearance.
- These effects led to reduced amyloid burden and improved cognitive function.
- MS4A4A-M159V variant and TREM2 deficiency abrogated these benefits.
Conclusions:
- MS4A4A plays a critical role in modulating AD pathology through TREM2.
- MS4A4A represents a promising therapeutic target for Alzheimer's disease.
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