期刊
EMBO MOLECULAR MEDICINE
卷 12, 期 3, 页码 -出版社
WILEY
DOI: 10.15252/emmm.201910606
关键词
Alzheimer's disease; genetic risk; microglia; RNA-seq; single cell
资金
- Opening the Future campaign of the Leuven Universitair Fonds (LUF)
- Alzheimer Research Foundation (SAO-FRA) [P16017]
- Alzheimer's Association USA
- Alzheimer's Association [AARF-16-442853]
- FWO [G0C9219N]
- KU Leuven
- VIB
- Methusalem grant from KU Leuven
- Flemish Government
- Geneeskundige Stichting Koningin Elisabeth
- MRC
- Alzheimer Society
- Alzheimer Research UK
- [ANR-16-COEN-0007]
- Austrian Science Fund (FWF) [P16017] Funding Source: Austrian Science Fund (FWF)
- MRC [UKDRI-1004] Funding Source: UKRI
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/PS1(L166P) and Thy-TAU22. A unique gene expression module, highly enriched for AD risk genes, is specifically responsive to A beta 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 A beta. Single microglia sequencing confirms that A beta, 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 A beta pathology, placing AD genetic risk downstream of the amyloid pathway but upstream of TAU pathology.
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