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Published on: January 30, 2014
MS4A6A/Ms4a6d deficiency disrupts neuroprotective microglia functions and promotes inflammation in Alzheimer's
Hai-Shan Jiao1, Yi-Jun Ge1, Liang-Yu Huang2
1Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, National Center for Neurological Disorders, 12Th Wulumuqi Zhong Road, Shanghai, 200040, China.
Background:
Alzheimer's disease (AD) is the most common type of dementia. 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 evidences 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.
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 reduced amyloid clearance in the brain. Immunostaining from postmortem AD patients brain revealed selective expression of MS4A6A in microglia. In APP/PS1 mice lacking Ms4a6d, microglia showed markedly diminished 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 in human microglia cell line promoted gene expression related to plaque-associated responses and diminished inflammation signatures.
Conclusions:
Our findings reveal that Ms4a6d deficiency suppresses neuroprotection and worsens neuroinflammation. Sufficient Ms4a6d maybe beneficial for boosting amyloid-related responses and suppressing inflammation in microglia, 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.
Insights
Genetic variations in MS4A6A impact Alzheimer's disease (AD) risk. Boosting MS4A6A may offer a novel therapeutic strategy by enhancing amyloid clearance and reducing neuroinflammation in AD patients.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- Alzheimer's disease (AD) is the most common dementia, with genetic factors influencing risk.
- Microglia-associated genes, including MS4A6A, are implicated in AD pathogenesis.
- Elevated MS4A6A levels and their correlation with neuropathology suggest a role in AD, yet the underlying mechanisms remain unelucidated.
Purpose of the Study:
- To investigate the association between MS4A6A gene polymorphisms and Alzheimer's disease (AD) risk.
- To explore the functional role of MS4A6A in AD pathogenesis, particularly concerning microglial function and neuroinflammation.
- To evaluate the therapeutic potential of modulating MS4A6A in AD.
Main Methods:
- Meta-genome-wide association analysis of 734,121 subjects to identify MS4A6A polymorphisms linked to AD risk.
- Correlation analysis of MS4A6A expression with cerebrospinal fluid AD biomarkers in a human cohort.
- Generation and analysis of a Ms4a6d-deficient APP/PS1 mouse model using microscopy, biochemistry, and behavioral assessments.
Main Results:
- Identified novel MS4A6A mutations associated with altered AD risk and cerebrospinal fluid β-amyloid levels.
- Demonstrated that Ms4a6d deficiency in mice impairs amyloid clearance by microglia, increasing plaque burden and synaptic damage.
- Showed that Ms4a6d deficiency exacerbates neuroinflammation by disinhibiting NF-κB signaling in microglia and astrocytes.
Conclusions:
- Ms4a6d deficiency impairs neuroprotection and exacerbates neuroinflammation in Alzheimer's disease models.
- Sufficient Ms4a6d expression enhances microglial amyloid clearance and suppresses inflammation, suggesting therapeutic potential.
- Elevated MS4A6A in AD patients may be compensatory; boosting MS4A6A presents a promising therapeutic strategy for Alzheimer's disease.
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