Discovery of novel mitophagy activators for Alzheimer´s disease

Background

Alzheimer’s disease (AD) affects over 35 million people worldwide and causes formidable economic challenges. Since 2003, over 250 drug candidates, predominantly targeting two pathological proteins, amyloid-β (Aβ) and pathological Tau, have been tested in clinical trials for AD, but most of them have failed. There is a need to pursue new mechanistic studies in order to better understand the underlying causes of AD, and to discover new drug targets. Mitochondria operate as cellular “powerhouses” and play a pivotal role in neuroplasticity and memory, thus dysfunction in mitochondria can impair neuronal function and trigger neurodegeneration. The homeostatic maintenance of functional mitochondria is crucial for neuronal health and survival. Mitochondria are constantly exposed to stress and damage; to cope, dysfunctional mitochondria must be specifically and efficiently eliminated via a cellular self-clearance system, “mitophagy”. Mitophagy is impaired in the elderly, leading to the accumulation of damaged mitochondria. The impaired energy production brought about by these dysfunctional mitochondria manifests in the senescence, inflammation, and neuronal loss seen in the elderly, and in AD patients. Large-scale omics and functional studies using post-mortem brain tissues and iPSCs from AD identified impaired mitochondrial function and impairment of mitochondria-related pathways as major changes in AD. My group was one of the very first research teams to propose defective mitophagy as a key driver in AD initiation and progression and to demonstrate its causative role; we have demonstrated the effectiveness of mitophagy induction in inhibiting memory loss in multiple AD animal models (Trends Neurosci 2017; Nature Neurosci 2019; Cell Metabolism 2019; Nature Biomedical Engineering 2022). Previous work has highlighted how impaired mitophagy coincides with the behavioural and pathological development and progression of AD. Genetic and pharmacological promotion of mitophagy rescued cognitive decline in AD models, and inhibited the phosphorylation of Tau (p-Tau) in both human cell lines and 3xTgAD mice. However, robust neuronal mitophagy inducers with clinical potential, that is to induce mitophagy but without causing mitochondrial damage at the same dose, is sparse. Very recently, we have established an artificial intelligence (named Fang-AI) plus wet lab validation platform, enabled us successful identification of two lead compunds as drug candidates for AD. This proposal aims to use the ‘Fang-AI’ plus our wet lab platform (C. elegans, mice and iPSCs) to swiftly identify new drug candidates for AD. As defective mitophagy is likely a shared cause of different neurodegenerative diseases (such as Parkinson’s disease/PD, Huntington’s disease/HTT, and Amyotrophic Lateral Sclerosis/ALS), turning up mitophagy via pharmaceutically approaches could be a druggable target for broad neurodegenerative diseases.