High-throughput testing of anti-aging and FDA approved drugs in genetically diverse invertebrate Alzheimer's models

Project Abstract Alzheimer’s disease (AD) is the leading cause of dementia, with incidence on the rise—clearly central to a global health crisis. Clinical symptoms often manifest as a progressive decline in cognitive ability and memory impairment but eventually leads to loss of control of vital functions. AD is a slow-developing neurodegenerative disease for which age is the leading risk factor indicating that aging interventions and lifespan extending drugs might be AD-effective. Although, hundreds of anti-aging compounds have been identified, very few of these compounds have been evaluated on animal models of AD. Our premise is that the AD models of the nematode C. elegans have much to contribute to the identification of lead candidate drugs that improve neuronal aging and protect against proteostasis disease. We propose to use a novel high-throughput technology to screen many FDA approved drugs and anti-aging compounds in C. elegans enabling us to test longevity-promoting compounds that will include a subset with potent effects against AD-related toxicity. AIM 1: Perform a screen on C. elegans AD models with lifespan-extension and FDA-approved drugs. In this aim, we plan to screen 300 anti-aging compounds and 200 FDA-approved drugs that target the hallmarks of aging on C. elegans AD models. The screen capitalizes on NemaLife’s high throughput screening platform with phenotypic end-points of mobility declines and survival. Hits will be confirmed by in vivo imaging of aggregates. This task will generate a compound lead series for AD drug development pipeline. AIM 2. Prioritize lead candidates by addressing critical gaps in preclinical AD drug discovery. Robust translation of drugs requires testing lead series with genetically diverse AD strains and also developing combination therapy to target multiple AD pathways. We will generate recombinant C. elegans strains to address genetic diversity in AD and plan to screen the most promising compounds and determine if interventions administered at early adult or late adult (onset of symptoms) stages are effective. Finally, a proof- of-principle combination study that involves compounds targeting hallmarks of aging will be piloted against the AD models. This multi-prong approach is expected to de-risk drug failure in mammalian AD models. In summary, we will use a novel NemaLife technology to identify a subset of pharmacological longevity interventions will exert neuroprotection against AD-relevant stresses. The outcome will establish both promising candidates for AD preclinical study and potentially clinical trials and a much-needed work-horse tool in drug discovery that prioritizes compounds for human AD.Project Narrative Alzheimer’s disease (AD) is devastating for victims, their families, and society, yet anti-AD treatments remain painfully elusive. Since age is a major risk factor for Alzheimer’s disease as well as other age- related chronic diseases, investigating drugs that target hallmarks of aging hold promise for AD therapeutics. Our plan combines a high-throughput microfluidic technology and genetically diverse nematode strains that feature Alzheimer’s disease-associated stresses to screen and identify repurposed drugs and anti-aging compounds that are both neuroprotective and extend lifespan, which would be considered priority follow-up interventions for anti-AD impact in higher organisms.