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Novel Alzheimer risk genes determine the microglia response to amyloid‐β but not to TAU pathology

Sierksma, A; Lu, A; Mancuso, R; Fattorelli, N; Thrupp, N; Salta, E; Zoco, J; ... Fiers, M; + view all (2020) Novel Alzheimer risk genes determine the microglia response to amyloid‐β but not to TAU pathology. EMBO Molecular Medicine , Article e10606. 10.15252/emmm.201910606. (In press). Green open access

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Abstract

Polygenic risk scores have identified that genetic variants without genome‐wide significance still add to the genetic risk of developing Alzheimer's disease (AD). Whether and how subthreshold risk loci translate into relevant disease pathways is unknown. We investigate here the involvement of AD risk variants in the transcriptional responses of two mouse models: APPswe/PS1L166P and Thy‐TAU22. A unique gene expression module, highly enriched for AD risk genes, is specifically responsive to Aβ but not TAU pathology. We identify in this module 7 established AD risk genes (APOE, CLU, INPP5D, CD33, PLCG2, SPI1, and FCER1G) and 11 AD GWAS genes below the genome‐wide significance threshold (GPC2, TREML2, SYK, GRN, SLC2A5, SAMSN1, PYDC1, HEXB, RRBP1, LYN, and BLNK), that become significantly upregulated when exposed to Aβ. Single microglia sequencing confirms that Aβ, not TAU, pathology induces marked transcriptional changes in microglia, including increased proportions of activated microglia. We conclude that genetic risk of AD functionally translates into different microglia pathway responses to Aβ pathology, placing AD genetic risk downstream of the amyloid pathway but upstream of TAU pathology.

Type: Article
Title: Novel Alzheimer risk genes determine the microglia response to amyloid‐β but not to TAU pathology
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.15252/emmm.201910606
Publisher version: http://dx.doi.org/10.15252/emmm.201910606
Language: English
Additional information: This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: Alzheimer's disease, RNA-seq, genetic risk, microglia, single cell
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UK Dementia Research Institute HQ
URI: https://discovery.ucl.ac.uk/id/eprint/10090158
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