Genetic variability in response to amyloid beta deposition influences Alzheimer’s disease risk

作者：Derviş A. Salih, Sevinç Bayram, Sebastian Guelfi, Regina H. Reynolds, Maryam Shoai, Mina Ryten, Jonathan Brenton, David Zhang, Mar Matarín, Juan A. Botía, Runil Shah, Keeley J. Brookes, Tamar Guetta‐Baranes, Kevin Morgan, Eftychia Bellou, Damian M. Cummings, Valentina Escott‐Price, John Hardy · 发表于：Brain Communications · 年份：2019 · DOI：10.1093/braincomms/fcz022 · 被引用次数：118 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Alzheimer's disease research and treatments、Neurological Disease Mechanisms and Treatments

Abstract Genome-wide association studies of late-onset Alzheimer’s disease risk have previously identified genes primarily expressed in microglia that form a transcriptional network. Using transgenic mouse models of amyloid deposition, we previously showed that many of the mouse orthologues of these risk genes are co-expressed and associated with amyloid pathology. In this new study, we generate an improved RNA-seq-derived network that is expressed in amyloid-responsive mouse microglia and we statistically compare this with gene-level variation in previous human Alzheimer’s disease genome-wide association studies to predict at least four new risk genes for the disease (OAS1, LAPTM5, ITGAM/CD11b and LILRB4). Of the mouse orthologues of these genes Oas1a is likely to respond directly to amyloid at the transcriptional level, similarly to established risk gene Trem2, because the increase in Oas1a and Trem2 transcripts in response to amyloid deposition in transgenic mice is significantly higher than both the increase of the average microglial transcript and the increase in microglial number. In contrast, the mouse orthologues of LAPTM5, ITGAM/CD11b and LILRB4 (Laptm5, Itgam/CD11b and Lilra5) show increased transcripts in the presence of amyloid plaques similar in magnitude to the increase of the average microglial transcript and the increase in microglia number, except that Laptm5 and Lilra5 transcripts increase significantly quicker than the average microglial transcript as the p...