Skip to Main content Skip to Navigation
Journal articles

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

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.
Complete list of metadata

Cited literature [74 references]  Display  Hide  Download
Contributor : David Blum Connect in order to contact the contributor
Submitted on : Wednesday, January 22, 2020 - 8:50:58 PM
Last modification on : Wednesday, March 23, 2022 - 3:51:28 PM
Long-term archiving on: : Thursday, April 23, 2020 - 5:28:45 PM




Annerieke Sierksma, Ashley Lu, Renzo Mancuso, Nicola Fattorelli, Nicola Thrupp, et al.. Novel Alzheimer risk genes determine the microglia response to amyloid‐β but not to TAU pathology. EMBO Molecular Medicine, Wiley Open Access, 2020, pp.e10606. ⟨10.15252/emmm.201910606⟩. ⟨inserm-02450349⟩



Record views


Files downloads