Small Molecule Compound with Indole Moiety Protects Against Alzheimer’s Disease Pathology in C. elegans and Mammalian Cell Culture Models

Alzheimer\u27s disease (AD) is a progressive neurodegenerative disease and the leading cause of dementia in the elderly. In 2020, an estimated 5.8 million Americans 65 and older were living with Alzheimer\u27s dementia1. Currently, the disease has no cure, and extensive research continues to explore potential treatments. Because the pathogenesis of AD has been attributed, at least in part, to the extracellular aggregation and toxicity of the amyloid beta (Aβ) protein in the brain, discovering therapeutics that target this protein remains of interest. However, many past drug development programs and clinical trials that target Aβ aggregates have been unsuccessful. There is evidence that chemical compounds that extend longevity and those that decrease levels of neurodegeneration have significant overlap (Lithgow GJ, personal communication). Thus, the objective of this study was to gain insight into the mechanisms of potential therapeutics for the treatment of AD with a focus on the use of lifespan-extending small molecule compounds. These compounds were previously identified to extend lifespan in C. elegans, an effective model organism. We identified a small molecule compound with an indole moiety that showed protective effects against Aβ(1-42)-induced phenotypes in a C. elegans model of AD. This compound, however, did not demonstrate the ability to robustly extend lifespan in multiple worm species and strains, suggesting a dependency on genetic background. Upon testing this compound further in mammalian cell culture models, we demonstrated that it protected mouse microglia cells against Aβ(1-42)-induced inflammation and protected mouse hippocampal neurons against glutamate toxicity. Further studies demonstrated this compound alters markers of autophagy in both cell culture and C elegans. In summary, we identified a small molecule compound that shows potential neuroprotective effects, and supports the search for more therapeutic compounds that aid in the prevention of neurological disease