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Epigenome-Wide Association Study of the Interaction between Alzheimer’s disease and Systemic Infection

ABSTRACT: Although most Alzheimer’s disease (AD) cases are sporadic, with no known aetiology, the onset and progression of the disease has been widely linked with inflammation both in the periphery and within the brain. Indeed, many AD sufferers ultimately die with a systemic infection, and infections during life can increase the risk of developing dementia and the rate of cognitive decline in AD patients. However, the mechanistic pathways linking inflammatory processes to AD onset and progression are not known. This study will use an epigenomic approach to elucidate the molecular mechanisms involved in the brain in AD following systemic inflammation. A better understanding of the neurobiological pathways altered in AD during systemic inflammation could ultimately identify new pharmacological targets, potentially improving the lives of millions of AD sufferers worldwide. This work identifies molecular mechanisms that are altered in AD brain during systemic inflammation, which can then be functionally characterised and targeted in in vitro modelling systems.

ORGANISM(S): Homo sapiens

PROVIDER: GSE284764 | GEO | 2025/04/11

REPOSITORIES: GEO

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Project description:Alzheimer´s disease (AD) is the most common form of dementia. Over fifty years of intense research have revealed many key elements of the biology of this neurodegenerative disorder. However, our understanding of the molecular bases of the disease is still incomplete, and the available medical treatments for AD are mainly symptomatic and hardly effective. Indeed, the robustness of biological systems have revealed that the modulation of a single target is unlikely to yield the desired outcome, and we should move from gene-centric to systemic therapeutic strategies. Here, we present the complete characterization of three murine models of AD at different stages of the disease (i.e. onset, progression and advanced). To identify genotype-to-phenotype relationships, we combine the cognitive assessment of these mice with histological analyses and a full transcriptional and protein quantification profiling from hippocampus. Comparison between the gene and protein expression trends observed in AD progression and physiological ageing exposed certain commonalities, such as the upregulation of microglial and inflammation markers. However, although there is an accelerated ageing in AD models, there are other factors specifically associated with Aβ pathology. Despite the clear correlation between mRNA and protein levels of the dysregulated genes, we discovered a few proteins whose abundance increases with AD progression, while the corresponding transcript levels remain stable. Indeed, we show that at least two of these proteins, namely lfit3 and Syt11, co-localize with Aβ plaques in the brain. Finally, we derive specific Aβ-related molecular AD signatures, and we look for drugs able to globally revert them. We found two NSAIDs (dexketoprofen and etodolac) and two anti-hypertensives (penbutolol and bendroflumethiazide) that overturn the cognitive impairment in AD mice while reducing Aβ plaques in the hippocampus and partially restoring the physiological levels of AD signature genes to wild-type levels.

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Epigenome-Wide Association Study of the Interaction between Alzheimer’s disease and Systemic Infection

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