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Cell type-specific molecular analysis of epigenetic changes and transposable element derepression in Alzheimer's disease progression

Project description

Finding early cellular markers of Alzheimer’s disease to preclude symptoms

Alzheimer’s disease (AD) is the most common form of dementia. It is an irreversible, progressive neurodegeneration of the brain that impacts memory and cognitive skills, and evidence suggests that the brain changes may begin 20 years or more before the onset of symptoms. Death rates of AD are increasing whereas those for heart disease and cancer are declining. As the ageing population grows, diagnosing the onset of AD before irreversible damage occurs is a pressing public health challenge. The hippocampus is an area of the brain intricately linked to the short-term memory loss that is a hallmark of AD. The EU-funded CTS-TEs-ADprogress project is studying hippocampal cells from a well-established mouse model of AD to identify cell-type-specific changes in gene expression during onset and progression of AD. Insight could point to early cellular harbingers of AD.

Objective

Alzheimer’s disease (AD) is a major contributor to disease burden and healthcare costs worldwide. AD is usually diagnosed once symptoms like memory impairment become evident. However, at this point typical AD pathology such as Aβ plaques and cell death is already widespread, suggesting that molecular changes have occurred decades before symptom onset. With an increasingly aging population and no available treatments, it has become imperative to identify the molecular mechanisms underlying onset and progression of AD. Chronic environmental stress and age-associated changes in stress response have been associated as drivers of AD pathology. The epigenome plays a critical role in translating stress signals into a cellular response by influencing gene expression, which can either promote or inhibit cell survival. Several studies have shown that alterations in chromatin structure, including heterochromatin loss, and associated changes in gene expression contribute to neurodegeneration. In addition, neuronal death was also linked to transposable element (TE) dysregulation due to epigenetic changes, which can lead to changes in gene expression and insertional mutations due to transposition. However, our understanding of epigenetic changes at onset and during progression of AD pathology is very limited, as current studies have two major limitations: 1) lack of cell type resolution due to use of bulk tissue samples and 2) coverage of only few or only one disease stage.
Here, single-cell RNA-seq and ATAC-seq as well as CUT&RUN on isolated hippocampal neuron subtypes will be used to identify cell type-specific alterations of gene expression and gene regulatory mechanisms during onset and progression of AD pathology in the APP/PS1 mouse model. APP/PS1 mice are a well-established AD model, which recapitulates many characteristics of preclinical AD in human patients and thereby allows correlating the identified changes with the development of specific pathological hallmarks.

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Topic(s)

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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)

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Call for proposal

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(opens in new window) H2020-MSCA-IF-2019

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Coordinator

DEUTSCHES ZENTRUM FUR NEURODEGENERATIVE ERKRANKUNGEN EV
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 174 806,40
Address
VENUSBERG-CAMPUS 1/99
53127 BONN
Germany

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Region
Nordrhein-Westfalen Köln Bonn, Kreisfreie Stadt
Activity type
Research Organisations
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 174 806,40
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