Dataset Information

Functional Interaction between APOE4 and mutant APP promotes cerebrovascular changes in young animals

ABSTRACT: The Apolipoprotein E4 (ApoE4) allele is one of the strongest risk factors for late-onset Alzheimer’s disease (AD) and is associated with a breakdown of the blood-brain barrier and vascular dysfunction (Nation et al 2019; Liu and Bu 2022). Importantly, these vascular pathologies are exacerbated when APOE4 is coexpressed with familial mutations in APP or components of the γ-secretase complex (Montagne and Zlokovic 2021), suggesting that the interactions between APOE4 and AD mutations can drive progression of the disease. However, most studies have been done in aging animals and few look at the impact of APOE4 expression in young animals and how that potentially contributes toward late-stage disease susceptibility. Here, we examined the potential functional interaction between APP mutations and ApoE4 in the progression of AD pathophysiology by comparing the hippocampal transcriptomes of 3-month-old female mice of 4 different genotypes: AppNL-G-F/NL-G-F , which harbours three knock-in mutations in the humanised Aβ region of APP (APP-TKI; Saito et al., 2014), mice with a single allele of human ApoE4 knocked-in, ApoE4+/wt (ApoE4), crosses of these two mouse lines, to create AppNL-G-F/NL-G-F;Apoe4+/wt (double-mutant or DM) mice, and wild-type (WT) mice that served as controls. RNAseq revealed nascent microglial activation signatures in both APP-TKI and double mutant datasets, as well as subtle but significant differences between APP-TKI and double mutant in expression of a subset of vascular remodeling genes.

ORGANISM(S): Mus musculus

PROVIDER: GSE242751 | GEO | 2024/04/30

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Oxidative stress is a major risk factor for Alzheimer’s disease (AD), which is characterized by brain atrophy, amyloid plaques, neurofibrillary tangles, and loss of neurons. 8-Oxoguanine, a major oxidatively generated nucleobase highly accumulated in the AD brain, is known to cause neurodegeneration. In mammalian cells, several enzymes play essential roles in minimizing the 8-oxoguanine accumulation in DNA. MUTYH with adenine DNA glycosylase activity excises adenine inserted opposite 8-oxoguanine in DNA. MUTYH is reported to actively contribute to the neurodegenerative process in Parkinson and Huntington diseases and some mouse models of neurodegenerative diseases by accelerating neuronal dysfunction and microgliosis under oxidative conditions; however, whether or not MUTYH is involved in AD pathogenesis remains unclear. In the present study, we examined the contribution of MUTYH to the AD pathogenesis. Using postmortem human brains, we showed that various types of MUTYH transcripts and proteins are expressed in most hippocampal neurons and glia in both non-AD and AD brains. We further introduced MUTYH deficiency into AppNL-G-F/NL-G-F knock-in AD model mice, which produce humanized toxic amyloid-β without the overexpression of APP protein, and investigated the effects of MUTYH deficiency on the behavior, pathology, gene expression, and neurogenesis. MUTYH deficiency improved memory impairment in AppNL-G-F/NL-G-F mice, accompanied by reduced microgliosis. Gene expression profiling strongly suggested that MUTYH is involved in the microglial response pathways under AD pathology and contributes to the phagocytic activity of disease-associated microglia. We also found that MUTYH deficiency ameliorates impaired neurogenesis in the hippocampus, thus improving memory impairment. In conclusion, we propose that MUTYH, which is expressed in the hippocampus of AD patients as well as non-AD subjects, actively contributes to memory impairment by inducing microgliosis with poor neurogenesis in the preclinical AD phase and that MUTYH is a novel therapeutic target for AD, as its deficiency is highly beneficial for ameliorating AD pathogenesis.

Dataset Information

Functional Interaction between APOE4 and mutant APP promotes cerebrovascular changes in young animals

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets