Roles of compromised mitophagy in Alzheimers disease

Alzheimer's disease (AD) is the most common dementia worldwide. Patients with AD have a low quality of life. In Norway, it is expected that there are about 80,000 to 120,000 individuals with AD. There is no drug available to inhibit the progression or to cure the disease. This project aims to develop novel drug candidates for AD patients. Our breakthrough showed that targeting on the clearance of brain garbage (toxicant proteins and dysfunctional the human powerhouses, mitochondria)is likely to be a novel drug target. And accordingly, some novel drug candidates for AD have been developed: Fang EF et al., Nature Neuroscience 2019: https://pubmed.ncbi.nlm.nih.gov/30742114/ Xie C et al., Nature Biomedical Engineering, 2022: https://pubmed.ncbi.nlm.nih.gov/34992270/ News UiO: https://www.med.uio.no/klinmed/english/research/news-and-events/news/2022/new-foundation-for-treatment-of-alzheimers-disease Nature (2022 special issue on ageing): https://evandrofanglab.files.wordpress.com/2022/01/nature-2022_take-out-the-cellular-trash_elie-dolgin_autophagy.pdf VG (cover): https://mynoad100.files.wordpress.com/2022/01/vg2022_alzheimers-e28093-vg.pdf

The project (#262175) enables the Fang group to make significant impacts to the society: 1. Actual outcomes: many good scientific papers published, including two in the leading journals Nature Neuroscience 2019 (https://pubmed.ncbi.nlm.nih.gov/30742114/) and Nature Biomedical engineering 2022 (https://pubmed.ncbi.nlm.nih.gov/34992270/) 2. Trainings of the next generation young scientists: two graduates involved in the grant have secured competitive jobs. Dr. Yahyah Aman (now editor in Nature Ageing, London office) and Dr. Chenglong Xie (currently associate Professor in Wenzhou Medical University, China). 3. Putting Norway at the forefront of Alzheimer's research: Fang has been invited to give more than 50 talks at national and international levels. E.g., he has been invited to give talks in Cambridge, Oxford, University of Hong Kong, National University of Singapore, Imperial College London, King's College London.

Mitochondrial malfunction is a hallmark of ageing and maintenance of a healthy mitochondrial pool may contribute to improvement of health-span and lifespan. Alzheimer's disease (AD) is one of the most common diseases in elderly (over 65) affecting 46.8 million individuals, and is an impending challenge for healthcare facilities and public resources. Currently there is no cure for AD and the failure of clinical trials for many anti-AD compounds, majorly target on amyloid hypothesis or tauopaghy, urgently request for novel mechanistic studies on AD. Emerging evidence suggests a crucial role of mitochondrial dysfunction in AD pathology, however the underlying molecular mechanisms are largely unexplored. Mitophagy is a subcellular process that removes damaged mitochondria thereby contributing to maintenance of mitochondrial quality. We recently reported compromised mitophagy induces neurodegeneration and accelerated ageing. Here we present preliminary evidence that mitophagy is compromised in both tau and Abeta AD worms (C. elegans). We therefore hypothesize that defective mitophagy contributes to disease initiation and progression in AD. The objectives of this project are to a) unveil molecular mechanisms of defective mitophagy in AD; b) develop novel mitochondrial proteins as early detection biomarkers of AD; and c) screen mitophagy-inducing anti-AD compounds, with a final aim at transforming the lives of AD patients. I have a strong track record of high impact publications, existing national and international collaborations, competitive advantage of unique reagents (AD|mitophagy animal models and drug-screen libraries), and preliminary data that ensure the feasibility of this project. In summary, I aim to establish an internationally competitive laboratory with studies focusing on mechanisms of mitophagy and its roles in neurodegeneration and ageing, especially AD, and finally develop novel therapeutic strategies for these diseases.