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Increased intron retention is a post-transcriptional signature associated with progressive ageing and Alzheimer’s disease

ABSTRACT: Intron retention (IR) may affect gene expression and protein functions during development and age-onset diseases. However, it remains unclear if IR undergoes spatial or temporal changes during different stages of ageing or neurodegenerative disorders like Alzheimer’s disease (AD). By profiling mRNA species across different ages of Drosophila heads, we observed significant increase in the level of IR of many conserved genes as animals aged. Interestingly, distinct sets of genes are affected at different stages of adult fly life with IR occurring at several AD-associated genes in old adult. This suggests that alteration of proper protein functions by IR during ageing may lead to AD pathogenesis. Consistent with this notion, analyses of healthy human ageing brains and different AD datasets revealed similar increased aberrant IR activities in many AD-curated genes. Taken together, our data suggest that increase IR during ageing may be the driver for late-onset sporadic AD.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE110349 | GEO | 2020/02/19

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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Increased intron retention is a post-transcriptional signature associated with progressive ageing and Alzheimer’s disease

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