Genetic variability in response to amyloid beta deposition influences Alzheimer’s disease risk

Abstract

Genome-wide association studies of late-onset Alzheimer’s disease risk have previously identified genes primarily expressed in microglia that form a transcriptional network. Using transgenic mouse models of amyloid deposition, we previously showed that many of the mouse orthologues of these risk genes are co-expressed and associated with amyloid pathology. In this new study, we generate an improved RNA-seq-derived network that is expressed in amyloid-responsive mouse microglia and we statistically compare this with gene-level variation in previous human Alzheimer’s disease genome-wide association studies to predict at least four new risk genes for the disease (OAS1, LAPTM5, ITGAM/CD11b and LILRB4). Of the mouse orthologues of these genes Oas1a is likely to respond directly to amyloid at the transcriptional level, similarly to established risk gene Trem2, because the increase in Oas1a and Trem2 transcripts in response to amyloid deposition in transgenic mice is significantly higher than both the increase of the average microglial transcript and the increase in microglial number. In contrast, the mouse orthologues of LAPTM5, ITGAM/CD11b and LILRB4 (Laptm5, Itgam/CD11b and Lilra5) show increased transcripts in the presence of amyloid plaques similar in magnitude to the increase of the average microglial transcript and the increase in microglia number, except that Laptm5 and Lilra5 transcripts increase significantly quicker than the average microglial transcript as the plaque load becomes dense. This work suggests that genetic variability in the microglial response to amyloid deposition is a major determinant for Alzheimer’s disease risk, and identification of these genes may help to predict the risk of developing Alzheimer’s disease. These findings also provide further insights into the mechanisms underlying Alzheimer’s disease for potential drug discovery.

Tensor decomposition of stimulated monocyte and macrophage gene expression profiles identifies neurodegenerative disease-specific trans-eQTLs

“…These findings confirm previous results in the p25/Cdk5 model of neurodegeneration where a reactive microglia phenotype with activated IFN pathway was found [34]. More recently, Salih et al [33] identified a number of interferon signaling genes to be in co-expression network that is expressed in amyloid-responsive mouse microglia, including Oas and Ifit family members, and transcription factors such as Irf7 and Stat. The authors further found that Alzheimer's disease loci colocalize with cis-eQTLs targeting OAS1 in interferon-γ stimulated iPSC-derived macrophages.…”

“…Component 22 is highly enriched for a number of genes in the Type 1 interferon-signaling, defense response to virus, and complement activation pathways ( Fig 2E). A number of studies have linked genes from these functional categories to Alzheimer's disease [33][34][35], autism [36,37] and lupus [13]. Interestingly, we discovered that this component is also a trans-eQTL for Alzheimer's disease susceptibility loci (see below).…”

INPP5D Expression is Associated with Risk for Alzheimer’s Disease and Induced by Plaque-Associated Microglia

“…We observed similar findings in the 5xFAD amyloidogenic model, which exhibited an increase in gene and protein expression levels of Inpp5d with disease progression, predominately in plaque-associated microglia, suggesting induction of Inpp5d in plaqueproximal microglia. Similarly, a recent study reported that Inpp5d is strongly correlated with amyloid plaque deposition in the APPPS1 mouse model [25,26]. These findings are consistent with the observation of microgliosis in both AD and its mouse models.…”

Antiviral Immune Response in Alzheimer’s Disease: Connecting the Dots

“…IFN was shown to be required for sustaining microglial activation since suppression of IFN signaling significantly reduced the levels of CD68 and Clec7a, markers for microglial activation, and shifted the morphology of microglia toward homeostatic form ( Roy et al, 2020 ). Intriguingly, polymorphisms of ISGs, including OAS1 , ITGAM , LAPTM5 , and LILRB4 , were conjointly identified as a significant risk factor for AD, implicating IFN pathway as a genetic modifier ( Salih et al, 2019 ).…”

“…On the other hand, LOAD is a polygenic disease, where a number of risk polymorphism and rare variants exert their functions from microglia and/or involved in immunity ( Zhang et al, 2013 ; Huang et al, 2017 ; Kunkle et al, 2019 ). The implication of ISGs as risk factor of AD ( Salih et al, 2019 ) together with IFN upregulation in aging brain suggest that IFN pathway may have a profound influence on AD pathogenesis ( Figure 2 ).…”