Objective:

To investigate the associations between microglia-specific gene MS4A6A and Alzheimer's disease and the underlying mechanisms.

Background:

Genetic polymorphisms are associated with altered risks of AD onset, pointing to biological processes and potential targets for interventions. Consistent with the important roles of microglia in AD development, genetic mutations of several genes expressed on microglia have been identified as risks for AD. Emerging evidence indicate that the expression of a microglia-specific gene MS4A6A is thought to be associated with AD, since AD patients show upregulation of MS4A6A, and its levels correlate with the severity of clinical neuropathology. However, the mechanism linking MS4A6A and AD has not been experimentally studied.

Design/Methods:

We performed a meta genome-wide association analysis with 734,121 subjects to examine the associations between polymorphisms of MS4A6A with AD risks. In addition, we analyzed the correlation between MS4A6A and AD-related cerebrospinal fluid biomarkers from our own cohort. Furthermore, we for the first time generated a Ms4a6d deficient APP/PS1 model, and systematically examined pathological changes using high-resolution microscopy, biochemistry, and behavioral analysis.

Results:

We identified several new mutations of MS4A6A with altered AD risks and discovered specific correlation for some of them with the amount of β-amyloid in cerebrospinal fluid. Protective variant of MS4A6A is associated with elevated expression of the gene. Deficient Ms4a6d led to markedly diminished microglia envelopment and phagocytosis of amyloid, leading to increased plaque burden, less compact structure, and more severe synaptic damage. Importantly, Ms4a6d deficiency markedly exacerbated inflammatory responses in both microglia and astrocytes  by disinhibiting NF-κB signaling. Overexpressing MS4A6A promoted gene expression related to plaque-associated responses and diminished inflammation signatures.

Conclusions:

Our findings reveal that Ms4a6d deficiency suppresses neuroprotection and worsens neuroinflammation, making it superior than previously reported candidates for microglia modulation. Thus, the elevated MS4A6A levels in AD are likely compensatory and boosting MS4A6A could be an effective treatment.