Using geroscience to understand and treat Alzheimer's disease

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Abstract: There are no effective treatments for age-dependent neurodegenerative conditions such as Alzheimer's disease (AD). To address this major public health crisis, the National Alzheimer's Project Act (NAPA) was passed to “find effective interventions to treat and prevent AD and related dementias by 2025.” To achieve this goal in 5 years one or more effective drugs are required, likely sourced from repurposed drugs that are the basis of this application. Dementias are diseases that occur with age. Therefore, aging must be incorporated into the drug target validation strategy to ensure that the target mechanism remains active in aged individuals and to facilitate an understanding of the interaction between aging and AD. The recognition of this fact led to the NOT-AG-18-051 initiative with one goal of “employing a lifespan approach to understand the mechanisms of protective and risk factors” for AD. In this application, we formally address the goals of both initiatives by integrating lifespan studies with an age-related phenotypic screening platform that has yielded compounds that extend lifespan (geroprotectors), one of which is now in AD clinical trials. During the last decade a novel phenotypic screening platform based upon 5 toxicities associated with the aged brain was used to identify compounds that have therapeutic efficacy in multiple models of neurodegeneration and dementia. Surprisingly, these new synthetic compounds as well as their precursors slow aging in mice, keeping them younger at both the gene transcription and metabolomics levels and extend lifespan in other model organisms. The molecular target of one compound, J147, is identical to the target of a compound that extends lifespan in C. elegans. J147 has since been used in a 'chemical biology' approach to understand fundamental aspects of aging itself, for it engages essentially all of the known molecular pathways associated with the geroprotectors metformin and rapamycin as well as caloric restriction. Because of these new observations, we reasoned that by integrating lifespan studies in C. elegans with our novel phenotypic screening platform we could efficiently identify additional new aging pathways as well as AD drugs and drug targets. To accelerate the time needed to bring any discoveries to the clinic we will screen the ReFRAME library. This unique library consists of 12,000 compounds developed by the pharmaceutical industry, including nearly all that have ever been in man and those registered as investigational drug candidates. These drugs will initially be screened in the neurotoxicity assay used as our primary screen in previous drug discovery efforts. Positive hits will then be assayed for longevity in C. elegans. When necessary, target identification will be carried out as we have done in the past. Finally, pathway validation studies will be done in two very distinct mouse models of aging and dementia. This collaborative effort between three laboratories uses a new approach to understand the relationship between aging and dementia and the molecular pathways involved, with the likelihood of identifying new AD drugs.