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DNA rEpair impaired Mice with accElerated Neurodegeneration as Tool to Improve Alzheimer therapeutics

DNA rEpair impaired Mice with accElerated Neurodegeneration as Tool to Improve Alzheimer therapeutics

Objective

Alzheimer’s disease (AD) affects worldwide ~50 million people. Preclinical research relies mainly on transgenic mouse models overexpressing mutant human proteins that are altered in <5% of AD cases (e.g. β-amyloid and tau), however, despite prominent protein aggregates, they fail to show the dramatic neurodegeneration and cognitive decline of patients, indicating that plaques and tangles may not be the only requirement for AD. Age is the most determining factor in AD, but is poorly represented in current AD models.
Generating bona fide mouse models for various human DNA repair syndromes we have disclosed a very strong connection between DNA damage, repair and aging including dramatic neurodegeneration. Within the context of ERC-DamAge we discovered striking parallels in neurodegeneration, progressive cognitive decline and genome-wide expression profiles of repair-deficient Ercc1Δ/- mice and human AD. The similarities in expression profiles are an order of magnitude higher than current AD mouse models. We discovered that nutritional interventions can spectacularly delay neurodegeneration, opening realistic perspectives for combating AD and other neurodegenerative disorders. The primary goal of this application is to complete the characterization of the mouse mutants as a valid model for AD by a detailed quantitative comparison of all RNA classes of relevant brain compartments of Ercc1Δ/- mutants and AD patients. This not only provides the final PoC, but also an unparalleled resource for pathway analysis, target identification and biomarkers for monitoring disease progression and effects of any intervention. This application will be instrumental to facilitate transition to a valid AD model for pharmaceutical companies enabling development of effective medication for prevention and/or therapy. This proposal addresses a huge unmet medical need worldwide, which seriously affects QoL, challenges health care systems, and offers unprecedented socio-economical opportunities.
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Host institution

ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM

Address

Dr Molewaterplein 40
3015 Gd Rotterdam

Netherlands

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 150 000

Beneficiaries (1)

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ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM

Netherlands

EU Contribution

€ 150 000

Project information

Grant agreement ID: 665335

Status

Closed project

  • Start date

    1 July 2015

  • End date

    31 December 2016

Funded under:

H2020-EU.1.1.

  • Overall budget:

    € 150 000

  • EU contribution

    € 150 000

Hosted by:

ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM

Netherlands