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Identification of a rare coding variant in TREM2 in a Chinese individual with Alzheimer's disease
Luke W Bonham1, Daniel W Sirkis2, Jia Fan1,3
1a Memory and Aging Center, Department of Neurology , University of California, San Francisco , San Francisco , CA , USA.
Abstract:
Rare variation in the TREM2 gene is associated with a broad spectrum of neurodegenerative disorders including Alzheimer's disease (AD). TREM2 encodes a receptor expressed in microglia which is thought to influence neurodegeneration by sensing damage signals and regulating neuroinflammation. Many of the variants reported to be associated with AD, including the rare R47H variant, were discovered in populations of European ancestry and have not replicated in diverse populations from other genetic backgrounds. We utilized a cohort of elderly Chinese individuals diagnosed as cognitively normal, or with mild cognitive impairment or AD to identify a rare variant, A192T, present in a single patient diagnosed with AD. We characterized this variant using biochemical cell surface expression assays and found that it significantly altered cell surface expression of the TREM2 protein. Together these data provide evidence that the A192T variant in TREM2 could contribute risk for AD. This study underscores the increasingly recognized role of immune-related processes in AD and highlights the importance of including diverse populations in research to identify genetic variation that contributes risk for AD and other neurodegenerative disorders.
Insights
A rare TREM2 gene variant, A192T, was identified in a Chinese Alzheimer's disease (AD) patient. This variant significantly impacts TREM2 protein expression, suggesting a potential role in AD risk within diverse populations.
Area of Science:
- Neurogenetics
- Immunology
- Alzheimer's Disease Research
Background:
- Rare TREM2 gene variants are linked to neurodegenerative diseases like Alzheimer's disease (AD).
- Previous AD-associated TREM2 variants were mainly identified in European populations.
- TREM2, a microglial receptor, plays a role in sensing damage and regulating neuroinflammation.
Purpose of the Study:
- To identify and characterize rare TREM2 variants in a Chinese cohort.
- To investigate the functional impact of a novel TREM2 variant (A192T) on TREM2 protein expression.
- To explore the contribution of diverse genetic backgrounds to AD risk.
Main Methods:
- Analysis of a cohort of elderly Chinese individuals (cognitively normal, mild cognitive impairment, AD).
- Identification of the A192T TREM2 variant in an AD patient.
- Biochemical cell surface expression assays to assess TREM2 protein function.
Main Results:
- The A192T variant was identified in a single AD patient from the Chinese cohort.
- Biochemical assays demonstrated that A192T significantly alters TREM2 cell surface expression.
- This finding suggests A192T may contribute to AD risk.
Conclusions:
- The A192T TREM2 variant may confer risk for Alzheimer's disease.
- Immune system processes are increasingly recognized as critical in AD pathogenesis.
- Research including diverse populations is essential for identifying genetic risk factors for neurodegenerative disorders.