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.
Highlights
All the known mutations in genes causing early-onset Alzheimer’s disease alter amyloid precursor protein (APP) processing such that amyloid deposition becomes more likely (Hardy and Selkoe, 2002)
Similar to our findings with the initial microarray analysis, the RNA-seq analysis revealed a microglial module of genes that showed a strong correlation with amyloid beta (Ab) deposition, and contained the mouse orthologues of the identified genome-wide association studies (GWAS) loci TREM2, ABI3, CD33, INPP5D, MS4A6D, SPI1/PU.1, PLCG2, GAL3ST4, RIN3, HLA and APOE (Supplementary Table 1), verifying the relevance of this gene network to the human condition
Our hypothesis is that this network contains most of the genes that the microglia need to respond to amyloid plaques, including genes necessary for increases in cell number and activation
Summary
All the known mutations in genes causing early-onset Alzheimer’s disease alter amyloid precursor protein (APP) processing such that amyloid deposition becomes more likely (Hardy and Selkoe, 2002). Trem expression showed a strong correlation with the expression of a network of genes in the innate immune system suggesting Trem is a ‘hub’ gene, and may regulate the expression of the entire network This immune module of genes showed a remarkable positive correlation to amyloid deposition (Matarin et al, 2015), and contained orthologues of other already established Alzheimer’s disease risk genes such as Abca and Ms4a6d (Lambert et al, 2013). Mouse microglia clearly respond to plaques in a manner where the genes co-expressed within these microglia relate closely to the genes that are relevant in human disease These observations suggest that this innate immune network that is expressed by these amyloid-responsive microglia may be used to predict future risk genes for Alzheimer’s disease
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