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Alzheimer's disease-related dysregulation of mRNA translation causes key pathological features with ageing

ABSTRACT: Alzheimer's disease-related dysregulation of mRNA translation causes key pathological features with ageing

PROVIDER: PRJNA642886 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12422542_1.fastq.gz	Fastqsanger.gz
	SRR12422542_2.fastq.gz	Fastqsanger.gz
	SRR12422543_1.fastq.gz	Fastqsanger.gz
	SRR12422543_2.fastq.gz	Fastqsanger.gz
	SRR12422544_1.fastq.gz	Fastqsanger.gz

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Alzheimer's disease-related dysregulation of mRNA translation causes key pathological features with ageing.

Project description:Alzheimer's disease (AD) is characterised by Aβ and tau pathology as well as synaptic degeneration, which correlates best with cognitive impairment. Previous work suggested that this pathological complexity may result from changes in mRNA translation. Here, we studied whether mRNA translation and its underlying signalling are altered in an early model of AD, and whether modelling this deficiency in mice causes pathological features with ageing. Using an unbiased screen, we show that exposure of primary neurons to nanomolar amounts of Aβ increases FMRP-regulated protein synthesis. This selective regulation of mRNA translation is dependent on a signalling cascade involving MAPK-interacting kinase 1 (Mnk1) and the eukaryotic initiation factor 4E (eIF4E), and ultimately results in reduction of CYFIP2, an FMRP-binding protein. Modelling this CYFIP2 reduction in mice, we find age-dependent Aβ accumulation in the thalamus, development of tau pathology in entorhinal cortex and hippocampus, as well as gliosis and synapse loss in the hippocampus, together with deficits in memory formation. Therefore, we conclude that early stages of AD involve increased translation of specific CYFIP2/FMRP-regulated transcripts. Since reducing endogenous CYFIP2 expression is sufficient to cause key features of AD with ageing in mice, we suggest that prolonged activation of this pathway is a primary step toward AD pathology, highlighting a novel direction for therapeutic targeting.

| S-EPMC7297996 | biostudies-literature

Alzheimer's disease-related dysregulation of mRNA translation causes key pathological features with ageing

Project description:Primary rat cortical neurons and treated with AB for 24h. RNA-seq on total and ribosome-enriched sucrose cushion

2020-06-29 | GSE149540 | GEO

Microarray analysis of the astrocyte transcriptome in the ageing brain: relationship to Alzheimer's pathology and ApoE genotype

Project description:Astrocyte dysfunction impacts their normal function, including neuronal support, thereby contributing to neurodegenerative pathologies including Alzheimer's disease (AD). Therefore to understand the role of astrocytes in the pathogenesis of age-related disorders we analysed the gene expression profile of astrocytes with respect to Alzheimer-type pathology. The aim of the present study was to combine immuno-LCM and microarray analysis to characterise the astrocyte transcriptome at different Braak stages, and with respect to ApoE genotype, in post-mortem human temporal cortex sampled dervied from the Medical Research Council Cognitive Function and Ageing Study (MRC-CFAS).

2011-06-01 | GSE29652 | GEO

Endotype reversal as a novel strategy for screening drugs targeting familial Alzheimer's disease

Project description:While amyloid-β (Aβ) plaques are considered a hallmark of Alzheimer's disease, clinical trials focused on targeting gamma secretase, an enzyme involved in aberrant Aβ peptide production, have not led to amelioration of AD symptoms or synaptic dysregulation. Screening strategies based on mechanistic, multi-omics approaches that go beyond pathological readouts can aid in the evaluation of therapeutics. Using early-onset Alzheimer's (EOFAD) disease patient lineage PSEN1A246E iPSC-derived neurons, we performed RNA-seq to characterize AD-associated endotypes, which are in turn used as a screening evaluation metric for two gamma secretase drugs, the inhibitor Semagacestat and the modulator BPN-15606.

2022-01-27 | GSE95673 | GEO

Dysregulation of the epigenetic landscape of normal aging in Alzheimer's disease

Project description:Dysregulation of the epigenetic landscape of normal aging in Alzheimer's disease

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Hepatocyte polyploidization during ageing protects against transcriptional dysregulation and chronic liver disease

Project description:Hepatocyte polyploidization during ageing protects against transcriptional dysregulation and chronic liver disease

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Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease [3 of 3]

Project description:Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease [3 of 3]

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Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease [1 of 3]

Project description:Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease [1 of 3]

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Ageing-associated myelin dysfunction drives amyloid deposition in mouse models of Alzheimer's disease

Project description:Ageing-associated myelin dysfunction drives amyloid deposition in mouse models of Alzheimer's disease

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Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease [2 of 3]

Project description:Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease [2 of 3]

| PRJNA411990 | ENA

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