Featured ArticleSelecting for neurogenic potential as an alternative for Alzheimer's disease drug discovery

•Phenotypic screening against age-associated dementias used to identify neuroprotective compounds as potential AD drug candidates•J147 enhances memory, improves synaptic spine density, and stimulates neural stem and progenitor cell expansion from hES-derived NPCs.•CAD-031 is a more potent derivative of J147 with enhanced neurogenic potentiation in vitro and in vivo.•The combined properties of an AD drug-promoting neurogenic activity as well as neuroprotection hold great promise for future therapies.

IntroductionNeurons die in Alzheimer's disease (AD) and are not effectively replaced. An alternative approach to maintain nerve cell number is to identify compounds that stimulate the proliferation of endogenous neural stem cells in old individuals to replace lost neurons. However, unless a neurogenic drug is also neuroprotective, the replacement of lost neurons will not be sufficient to stop disease progression.MethodsThe neuroprotective AD drug candidate J147 is shown to enhance memory, improve dendritic structure, and stimulate cell division in germinal regions of the brains of very old mice. Based on the potential neurogenic potential of J147, a neuronal stem cell screening assay was developed to optimize derivatives of J147 for human neurogenesis.ResultsThe best derivative of J147, CAD-031, maintains the neuroprotective and memory enhancing properties of J147, yet is more active in the human neural stem cell assays.DiscussionThe combined properties of neuroprotection, neurogenesis, and memory enhancement in a single drug are more likely to be effective for the treatment of age-associated neurodegenerative disorders than any individual activity alone.