Ronald M. Loeb Center for Alzheimer's Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Ronald M. Loeb Center for Alzheimer's Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Trends Neurosci. 2020 Dec;43(12):965-979. doi: 10.1016/j.tins.2020.10.002. Epub 2020 Oct 27.
Alzheimer's disease (AD) is a debilitating, chronic neurodegenerative disease. Genetic studies involving genome-wide association studies (GWAS) and meta-analysis have discovered numerous genomic loci associated with AD; however, the causal genes and variants remain unidentified in most loci. Integration of GWAS signals with epigenomic annotations has demonstrated that AD risk variants are enriched in myeloid-specific enhancers, implicating myeloid cells in AD etiology. AD risk variants in these regulatory elements modify disease susceptibility by regulating the expression of genes that play crucial roles in microglial phagocytosis. Several of these AD risk genes are specifically expressed in myeloid cells, whereas others are ubiquitously expressed but are regulated by AD risk variants within myeloid enhancers in a cell type-specific manner. We discuss the impact of established AD risk variants on microglial phagocytosis and debris processing via the endolysosomal system.
阿尔茨海默病（AD）是一种使人虚弱的、慢性的神经退行性疾病。涉及全基因组关联研究（GWAS）和荟萃分析的遗传研究发现了许多与 AD 相关的基因组位点；然而，在大多数位点中，因果基因和变体仍然未知。GWAS 信号与表观基因组注释的整合表明，AD 风险变体在髓系特异性增强子中富集，提示髓系细胞在 AD 发病机制中起作用。这些调节元件中的 AD 风险变体通过调节在小胶质细胞吞噬作用中发挥关键作用的基因的表达来改变疾病易感性。这些 AD 风险基因中的几个在髓系细胞中特异性表达，而其他基因则广泛表达，但通过髓系增强子中的 AD 风险变体以细胞类型特异性的方式进行调节。我们讨论了已确定的 AD 风险变体通过内溶酶体系统对小胶质细胞吞噬作用和碎片处理的影响。
