Whole transcriptome analysis of brain hippocampal tissue from young and old senescence-accelerated prone SAMP8 mice treated with control diet and J147-containing diet

AD drug discovery has rarely been addressed in the context of aging even though sporadic AD accounts for 99% of the cases. Phenotypic screens based upon old age-associated brain toxicities were used to develop the potent AD drug candidate J147. Here, we hypothesized that J147 would be effective against both brain aging and AD-associated pathology in rapidly aging SAMP8 mice, a model for early sporadic AD. An inclusive and integrative multi-omics approach was used to investigate protein expression, RNA expression, metabolite levels as well as cognition in old and young SAMP8 mice. J147 not only reduced the cognitive deficits and associated metabolic changes observed in old SAMP8 mice, it restored the levels of multiple markers of AD, vascular pathology, synaptic function, and inflammation to those approaching the young phenotype. Our data show that a drug candidate selected upon the basis of preventing old age-related brain toxicities also reduces AD-associated pathology. Overall design: The aim of this project was to investigate whether the AD drug candidate J147 protects SAMP8 mice from aging and AD-associated pathology and to assay the associated metabolic changes. Three three-month old male SAMP8 mice were fed with vehicle diet and three three-month old male SAMP8 mice with J147 diet until they reached ten months old. Four three-month old male SAMP8 mice were used as young control group.

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Currais A, Goldberg J, Farrokhi C, Chang M, Prior M, Dargusch R, Daugherty D, Armando A, Quehenberger O, Maher P, Schubert D