Integrated approach reveals diet, APOE genotype and sex affect immune response in APP mice

Abstract

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that is influenced by genetic and environmental risk factors, such as inheritance of ε4 allele of APOE (APOE4), sex and diet. Here, we examined the effect of high fat diet (HFD) on amyloid pathology and expression profile in brains of AD model mice expressing human APOE isoforms (APP/E3 and APP/E4 mice). APP/E3 and APP/E4 mice were fed HFD or Normal diet for 3months. We found that HFD significantly increased amyloid plaques in male and female APP/E4, but not in APP/E3 mice. To identify differentially expressed genes and gene-networks correlated to diet, APOE isoform and sex, we performed RNA sequencing and applied Weighted Gene Co-expression Network Analysis. We determined that the immune response network with major hubs Tyrobp/DAP12, Csf1r, Tlr2, C1qc and Laptm5 correlated significantly and positively to the phenotype of female APP/E4-HFD mice. Correspondingly, we found that in female APP/E4-HFD mice, microglia coverage around plaques, particularly of larger size, was significantly reduced. This suggests altered containment of the plaque growth and sex-dependent vulnerability in response to diet. The results of our study show concurrent impact of diet, APOE isoform and sex on the brain transcriptome and AD-like phenotype.

Genetic variability in response to Aβ deposition influences Alzheimer’s risk

“…1 and Table S2 (top 147 genes from a total of 1,584 genes with up-regulated expression as part of the immune module based on the topological overlap measure, TOM, see Methods). This network is broadly similar to the network derived from the analysis of the same RNA by microarray methods ( 9 ), and importantly closely resembles microglial networks published by other groups using different amyloid mouse models ( 13–17 ), suggesting this is a conserved network of genes that can be reliably identified using different methodologies. Trem2 forms a hub gene in our network indicating that Trem2 expression is highly correlated to many other genes in the network, and may drive the expression response of this network.…”

“…CXCL10 was found to increase in older people and in AD, and correlated with cognitive decline ( 36 ). LAPTM5 (lysosome-associated protein, transmembrane 5) is associated with amyloid pathology in transgenic mice ( 17 ), and LILRB4 (leukocyte immunoglobulin-like receptor, subfamily B, member 4), has also been shown to be increased with amyloid pathology and specifically associated with amyloid plaques ( 15, 37, 38 ). The functions of LAPTM5 and LILRB4 have not been well characterized, but are thought to suppress the activation of a variety of immune cells.…”

APOEgenotype affects metabolic and Alzheimer‐related outcomes induced by Western diet in female EFAD mice

“…One particularly relevant sex difference is that APOE4-associated AD risk exhibits a significant female bias (1,6,7). In AD transgenic models with human APOE knock-in, APOE4 female mice show greater levels of neuropathology than APOE4 males (9,10). The extent to which sex affects the increased risk of AD associated with obesity is less clear.…”

“…Parallel observations of a female bias in AD-related effects of APOE4 have been observed in rodent models. For example, in transgenic mouse models that include familial AD (FAD) transgenes and human APOE alleles, APOE4 mice exhibit a significantly higher b-amyloid (Ab) burden than APOE3 mice do, with the highest Ab observed in female APOE4 mice (9,10).…”

Algorithm for theoretical mapping of bio-strings for co-expression: bridging genotype to phenotype

“…As in a study co-expression of protein variants and inter-allelic effects were observed as genotype-phenotype (Shen et al, 2016). Integration was established among diet, APOE genotype and immune response (Nam et al, 2018). Host genotype and tumor phenotype was also mentioned to be mapped in case of breast cancer (Yu et al, 2015).…”