Open AccessNovel Alzheimer risk genes determine the microglia response to amyloid‐β but not to TAU pathology
Author(s) -
Sierksma Annerieke,
Lu Ashley,
Mancuso Renzo,
Fattorelli Nicola,
Thrupp Nicola,
Salta Evgenia,
Zoco Jesus,
Blum David,
Buée Luc,
De Strooper Bart,
Fiers Mark
Publication year - 2020
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201910606
Subject(s) - microglia , trem2 , genome wide association study , biology , gene , alzheimer's disease , clusterin , disease , genetics , neuroscience , medicine , pathology , inflammation , immunology , single nucleotide polymorphism , apoptosis , genotype
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: APP swe/ PS 1 L166P and Thy‐ TAU 22. 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 , INPP 5D , CD 33, PLCG 2 , SPI 1, and FCER 1G ) and 11 AD GWAS genes below the genome‐wide significance threshold ( GPC 2, TREML 2, SYK , GRN , SLC 2A5, SAMSN 1, PYDC 1, HEXB , RRBP 1, 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.