Repurposing a human drug to treat Alzheimer’s disease

Project Information

Re-TauAD

Grant agreement ID: 101069214

DOI

10.3030/101069214

Project closed

EC signature date 23 May 2022

Start date 1 June 2022

End date 30 November 2023

Funded under

• European Research Council (ERC)

Total cost

No data

EU contribution

€ 150 000,00

Coordinated by

DEUTSCHES ZENTRUM FUR NEURODEGENERATIVE ERKRANKUNGEN EV
Germany

Periodic Reporting for period 1 - Re-TauAD (Repurposing a human drug to treat Alzheimer’s disease)

Reporting period: 2022-06-01 to 2023-11-30

Summary of the context and overall objectives of the project

Dementia, caused by Alzheimer’s disease (AD) or related diseases, is a major cause of disability and dependency among older adults worldwide, affecting memory, cognitive abilities, and behavior, ultimately interfering with one’s ability to perform daily activities. The impact of dementia is not only significant in financial terms, but also represents substantial human costs to countries, societies, families and individuals. In 2019, dementia affected 55 million people worldwide, with a predicted increase to 78 million in 2030 and 139 million by 2050. However, no cure is currently available for AD or dementia.
The solution: Accumulation of the protein tau in the brain is a pathological hallmark of AD, and the decline of cognition in patients with AD closely correlates with the degree and site of tau pathology. Many pharmaceutical companies therefore target pathological tau for disease intervention, with a strong focus on the development of tau antibodies. A major limitation of the currently investigated tau antibodies is, however, that they cannot enter neurons and thus are unable to act where tau accumulation occurs. There is thus a clear need to develop drugs that inhibit tau aggregation inside neurons. My lab achieved a breakthrough towards the development of a drug that inhibits pathogenic tau accumulation by repurposing a small molecule for the treatment of AD. The aim of our PoC project is tovalidate the pre-clinical application of the drug in transgenic tau-overexpressing mice.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

We have established a colony of PS19 human tau transgenic mice and administered the drug RE01 at two different concentrations (WP1.1). First behavioural experiments have been performed and analysed for ~8 month old mice (WP1.2). Further behavioural experiments are ongoing and will be analysed in the coming months. Additionally, the duration of survival will be compared between RE01-treated mice and the control group (WP1.3). Once all animals have died or were sacrificed, we will also assess neuropathology in corresponding brain hemispheres by immunohistochemistry in the two treatment as well as the control group measuring tau aggregates, misfolded/aberrant tau, phosphorylated tau, neuron loss, microglia activation, astrogliosis and synapse density. We will also perform biochemical assessment of the impact of RE01 on tau pathology by measuring total tau, phosphorylated tau and aggregated tau levels in the three groups (WP1.3).

Because of a delay in breeding the transgenic mice, we could only start with the treatment in December 2022. Additionally, the tau transgenic mice started to display a phenotype only at 8-9 months of age and even at 12 months of age several transgenic mice are still alive. Because of these delays, we do not yet have the final analysis data for the treatment of the tau transgenic mice with RE01. However, we will continue to analyse the behavioural experiments, survival curve and neuropathology in the coming months, i.e. after the ERC PoC grant has already finished.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The drug RE01 had not been investigated before in the context of Alzheimer's disease. Our experiments are thus the first to test the drug RE01 in an animal model of Alzheimer's disease. In case we find positive effects of the drug RE01 on tau transgenic mouse behaviour/cognition, the studies may form the basis for a dedicated drug development program targeting tau misfolding and aggregation with small molecules.