小胶质细胞吞噬作用：深入阿尔茨海默病基因库。

Microglial efferocytosis: Diving into the Alzheimer's disease gene pool.

机构信息

Ronald 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; Department of Psychiatry and Behavioral Sciences, University of California San Francisco, San Francisco, CA, USA.

出版信息

Neuron. 2022 Nov 2;110(21):3513-3533. doi: 10.1016/j.neuron.2022.10.015.

DOI:10.1016/j.neuron.2022.10.015

PMID:36327897

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.

摘要

全基因组关联研究和功能基因组学研究将特定的细胞类型、基因和途径与阿尔茨海默病（AD）风险联系起来。特别是，AD 风险等位基因主要影响巨噬细胞中表达的基因的丰度或结构，从而影响其活性，这强烈表明小胶质细胞（大脑驻留的巨噬细胞）在 AD 的发病机制中起作用。这些基因汇聚在（内吞/吞噬作用、胆固醇代谢和免疫反应）途径上，这些途径在核心巨噬细胞功能（如吞噬作用）中起着关键作用。在这里，我们综述了这些途径，强调了最新的 AD 遗传学和基因组学研究中发现的相关基因，并描述了它们如何可能导致 AD 的发病机制。研究 AD 相关变体和基因在小胶质细胞中的功能影响对于阐明疾病风险机制和开发有效的治疗方法至关重要。