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

Salih, Dervis A.; Bayram, Sevinc; Guelfi, Sebastian; Reynolds, Regina H.; Shoai, Maryam; Ryten, Mina; Brenton, Jonathan W.; Zhang, David; Matarin, Mar; Botia, Juan A.; Shah, Runil; Brookes, Keeley J.; Guetta-Baranes, Tamar; Morgan, Kevin; Bellou, Eftychia; Cummings, Damian M.; Escott-Price, Valentina; Hardy, John

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Authors

Dervis A. Salih

Sevinc Bayram

Sebastian Guelfi

Regina H. Reynolds

Maryam Shoai

Mina Ryten

Jonathan W. Brenton

David Zhang

Mar Matarin

Juan A. Botia

Runil Shah

Keeley J. Brookes

Tamar Guetta-Baranes

Kevin Morgan

Eftychia Bellou

Damian M. Cummings

Valentina Escott-Price

John Hardy



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 plaque load becomes dense. This work suggests that genetic variability in the microglial response to amyloid deposition is a major determinant for Alzheimer’s disease risk, and identification of these genes may help to predict the risk of developing Alzheimer’s disease. These findings also provide further insights into the mechanisms underlying Alzheimer’s disease for potential drug discovery.

Citation

Salih, D. A., Bayram, S., Guelfi, S., Reynolds, R. H., Shoai, M., Ryten, M., …Hardy, J. (2019). Genetic variability in response to amyloid beta deposition influences Alzheimer’s disease risk. Brain Communications, 1(1), Article fcz022. https://doi.org/10.1093/braincomms/fcz022

Journal Article Type Article
Acceptance Date Sep 11, 2019
Online Publication Date Oct 10, 2019
Publication Date Jan 1, 2019
Deposit Date Nov 20, 2019
Publicly Available Date Nov 20, 2019
Journal Brain Communications
Electronic ISSN 2632-1297
Publisher Oxford University Press
Peer Reviewed Peer Reviewed
Volume 1
Issue 1
Article Number fcz022
DOI https://doi.org/10.1093/braincomms/fcz022
Public URL https://nottingham-repository.worktribe.com/output/3345426
Publisher URL https://academic.oup.com/braincomms/article/1/1/fcz022/5585002
Contract Date Nov 20, 2019

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