Identification of the neuroprotective Shc target in Alzheimer's and validation of the neuroprotective benefit of a set of small‐molecule Shc blockers

Abstract

AbstractBackgroundIncreased Shc expression has recently been linked to human AD progression. The human Shc locus has recently been identified as extremely important in the conversion from Mild Cognitive Impairment (MCI) to full Alzheimer's Disease (AD) [1]. Shc is more highly expressed in Hippocampus of human AD cases vs. Controls [2], and A‐beta increases Shc activity and gene expression in cells, and Shc knockdown reduces A‐beta toxicity [3]. Mice with Shc reduction resist AD and age‐related cerebrovascular dysfunction. It has been demonstrated that there is a significant benefit to PSAPP mice when Shc is genetically reduced, they have improved memory and cognition relative to PSAPP mice, and survive longer. Furthermore this improvement is with the same amyloid burden–thus Shc underexpression appears to neuroprotect downstream of the toxic A‐beta signal[4]. Furthermore, Shc reduced mice resist age‐related cerebrovascular dysfunction [5]. Under MTA we have received small molecules from Buto Corp, to identify their relative efficacy in cell and animal models of disease.MethodWe tested the neuroprotective potency of Shc blockers challenged with A‐beta in 384‐well plates. We also tested the anti‐inflammatory potency of Shc blockers, by measuring post A‐beta or LPS challenge to human microglial cells the expression of multiple inflammatory genes, including IL‐6, IL‐10, and Nos. We also tested the impact of Shc Blockers on memory loss in the ApoE4 mouse model of ADResultWe observe significant protection of several Shc blockers from A‐beta neurotoxicity. We observe significant protection of multiple Shc blockers from A‐beta or LPS mediated microglial inflammation. We observe significant protection from memory loss in the ApoE4 mouse model of AD by a molecule observed to be neuroprotective in Results 1 and 2.ConclusionThe data above suggest that small‐molecule Shc blockers are a novel therapeutic strategy for AD.