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

Abstract

Background: Thousands of SNPs associated with risk of Alzheimer's disease (AD) in genome-wide association studies (GWAS) do not reach genome-wide significance. When combined, they contribute however to a highly predictive polygenic risk score. The relevance of these subthreshold risk genes to disease, and how their combined predictive power translates into functionally relevant disease pathways, is unknown. We investigate here at the genome-wide level and in an unbiased way to what extent AD risk genes show altered gene expression in the context of increasing Aβ or Tau pathology in mouse models of AD. Methods:We used an existing GWAS data set to generate lists of candidate AD genes at different levels of significance. We performed transcriptomic analysis on wild-type and transgenic APP/PS1 (APPtg) and Thy-TAU22 (TAUtg) mouse models at early and late stage of disease. We used unbiased weighted gene co-expression network analysis (WGCNA) to identify clusters of co-regulated genes responsive to Aβ or TAU pathology. Gene set enrichment was used to identify clusters that were enriched for AD risk genes.Findings: Consistent and significant enrichment of AD risk genes was found in only one out of 63 coexpression modules. This module is highly responsive to Aβ but not to TAU pathology. We identify in this module 18 AD risk genes (p-value=9.0e-11) including 11 new ones, GPC2, TREML2, SYK, GRN, SLC2A5, SAMSN1, PYDC1, HEXB, RRBP1, LYN and BLNK. All are expressed in microglia, have a binding site for the transcription factor SPI1 (PU.1), and become significantly upregulated when exposed to Aβ.A subset regulates FC-gamma receptor mediated phagocytosis.Interpretation: Genetic risk of AD is functionally translated into a microglia pathway responsive to Aβ pathology. This insight integrates aspects of the amyloid hypothesis with genetic risk associated to sporadic AD.

Neuronal and glial 3D chromatin architecture illustrates cellular etiology of brain disorders

“…Consistent with this, we observed that AD risk genes that we identified here were enriched for a microglial co-expression module upregulated in AD postmortem brains (T-M3, Figure 4g) 39 . This module is different from the module associated with epigenetic dysregulation in AD (Figure 3g), suggesting that genetic risk factors and epigenetic regulation underscore different expression signatures in AD with distinct cellular specificities and likely causal relationships [49][50][51] .…”

Glioma-derived IL-33 orchestrates an inflammatory brain tumor microenvironment that accelerates glioma progression

“…In addition, we found that, microglia 6 (cluster 8) was uniquely enriched in the IL-33 − tumors (Fig. 10c) and expressed genes involved in antigen presentation 106,108 (e.g., Cd74, H2-Aa, and H2-Ab1 (Supplementary Fig. 8a, b, g)).…”

“…9a, b, d); (2) BMDM 4 (cluster 12), shows substantial expression of genes involved in interferon signaling, including Ifit2, Ifit3, and Irf7 (refs. 105,106,108 ; Fig. 10f and Supplementary Fig.…”

Spatial and temporal transcriptomics reveal microglia-astroglia crosstalk in the amyloid-β plaque cell niche of Alzheimer’s disease

“…GWAS studies show in fact that much of the risk of sporadic AD is associated with genes expressed in micro-and astroglia (Jansen et al, 2019). These genes are strongly up-or downregulated when exposed to amyloid deposition (Salih et al, 2018;Sala Frigerio et al, 2019;Sierksma et al, 2019). It is clear that we need more in depth study of the protective and harmful cellular reactions that occur in the course of AD.…”