Alzheimer's disease pYGSK3 pathophysiology and PTPRD positive allosteric modulators

Biomedical Research Institute Of New Mex, Albuquerque NM

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Abstract

Project Summary/Abstract Alzheimer's disease (AD) receives pathogenic contributions from genetics [1, 2] and from environmental influences that include dietary intake of flavanols > flavones [4-8]. Neurofibrillary tangles (NFTs) rich in hyperphosphorylated tau protein [10] are prominent features of AD neuropathology. NFT densities correlate well with the degree of AD dementia [15] [18] and are influenced by variation in the ApoE and PTPRD genes [3]. One approach to altering tau/NFT pathophysiology is to reduce activities of the kinases that hyper- phosphorylate tau. The glycogen synthase kinases GSK3? and GSK3? are prominent tau phosphorylators [19]. GSK3? and GSK3? are activated by phosphorylation of their own tyrosines (pY279 and pY216) by known tyrosine kinases [20] [21, 22]. Increasing activity of tyrosine phosphatase(s) that dephosphorylate and reduce activities of brain GSK3? and GSK3? thus provides a novel approach to reducing tau pathology in AD. Evidence (much developed with support from our first NIA supplement) now supports roles for: a) the receptor type protein tyrosine phosphatase PTPRD as both a i) key physiological phosphatase for phospho (pY) GSK3? and GSK3? and ii) novel target for decreasing pathological AD tau hyper- phosphorylation and b) flavanols as lead compound PTPRD positive allosteric modulators (PAMs) that increase this desired PTPRD activity. We will enhance this evidence and move toward translation by testing hypotheses that a) increased PTPRD dephosphorylation of GSK3? and GSK3? reduces the activities of these tau-hyperphosphorylating kinases with specificity, underlying PTPRD's genetic associations with NFT densities in AD brains and b) flavanols whose intake reduces AD incidence in aging [4-8] serve as PAMs for PTPRD's phosphatase, increase GSK3 dephosphorylation with specificity and provide a pathway for development of improved, specific PTPRD PAMs that can reduce progression to AD deficits during aging. We will test these hypothesis and support development and translation of PTPRD PAMs in several ways: 1) we will characterize the specificity of PTPRD effects by comparing i: rates of PTPRD dephosphorylation of pYGSK3? and pYGSK3? and ii: quercetin effects on these rates vs those for each of > 80 candidate neuronal PTPRD substrates. 3) We will synthesize and test novel flavanol analogs as improved PTPRD PAMs, nominating novel structures by in silico docking to the PAM vs catalytic sites on PTPRD's phosphatase, testing these structures in vitro, refining our in silico models and nominating/synthesizing/testing new structures on the basis of these results. For the best candidate positive allosteric modulators, we will test specificities vs other PTPRD substrate phosphopeptides and off-target sites of action of currently marketed drugs. We will test the most promising PTPRD PAMs in vivo for gross, histological or behavioral toxicities, biodistribution (including brain) and target engagement. We will expand validation of quercetin effects in aging 3xTg- AD mice and initiate studies to test novel PTPRD PAM(s) in this model. This work will advance our understanding of AD pathophysiology, validate novel approaches to PTPRD positive allosteric modulation and provide a basis for development of interventions that can prevent and/or treat key aspects of AD pathophysiology.