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Published on: December 26, 2016
Microglial efferocytosis: Diving into the Alzheimer's disease gene pool
Carmen Romero-Molina1, Francesca Garretti1, Shea J Andrews2
1Ronald M. Loeb Center for Alzheimer's Disease, 1 Gustave L. Levy Place, New York, NY 10029-6574, USA; Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Abstract:
Genome-wide association studies and functional genomics studies have linked specific cell types, genes, and pathways to Alzheimer's disease (AD) risk. In particular, AD risk alleles primarily affect the abundance or structure, and thus the activity, of genes expressed in macrophages, strongly implicating microglia (the brain-resident macrophages) in the etiology of AD. These genes converge on pathways (endocytosis/phagocytosis, cholesterol metabolism, and immune response) with critical roles in core macrophage functions such as efferocytosis. Here, we review these pathways, highlighting relevant genes identified in the latest AD genetics and genomics studies, and describe how they may contribute to AD pathogenesis. Investigating the functional impact of AD-associated variants and genes in microglia is essential for elucidating disease risk mechanisms and developing effective therapeutic approaches.
Insights
Alzheimer's disease (AD) risk is linked to genes in brain macrophages called microglia. These genes control pathways crucial for microglial function, suggesting a key role in AD.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- Genome-wide association studies (GWAS) and functional genomics link specific genes and pathways to Alzheimer's disease (AD) risk.
- AD risk alleles predominantly impact genes in macrophages, particularly microglia (brain-resident macrophages), implicating them in AD pathogenesis.
- These AD-associated genes converge on critical macrophage functions like endocytosis, phagocytosis, cholesterol metabolism, and immune response.
Purpose of the Study:
- To review pathways implicated in Alzheimer's disease (AD) pathogenesis by genetic and genomic studies.
- To highlight key genes identified in recent AD genetics and genomics research.
- To elucidate the role of microglial gene function in AD risk and therapeutic development.
Main Methods:
- Review of existing literature on Alzheimer's disease genetics and functional genomics.
- Analysis of gene pathways converging on microglial functions (e.g., efferocytosis, cholesterol metabolism, immune response).
- Integration of findings from GWAS and functional genomics studies related to AD risk alleles.
Main Results:
- AD risk genes primarily affect gene expression in macrophages, with a strong emphasis on microglia.
- Key pathways involved in AD pathogenesis include endocytosis/phagocytosis, cholesterol metabolism, and immune response.
- These pathways are critical for core microglial functions, suggesting their dysregulation contributes to AD.
Conclusions:
- Microglia play a central role in Alzheimer's disease (AD) etiology due to the impact of AD risk alleles on their gene activity.
- Understanding the functional consequences of AD-associated variants and genes in microglia is crucial.
- Targeting microglial pathways offers a promising avenue for developing effective Alzheimer's disease therapeutics.
