Alzheimer's disease pYGSK3 pathophysiology and PTPRD positive allosteric modulators

阿尔茨海默病 pYGSK3 病理生理学和 PTPRD 正变构调节剂

基本信息

批准号：
10286886
负责人：
George Richard Uhl
金额：
$ 34.94万
依托单位：
BIOMEDICAL RESEARCH INSTITUTE OF NEW MEX
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10286886
关键词：
3xTg-AD mouse Aging Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Apolipoprotein E Behavioral Binding Binding Sites Biodistribution Biological Availability Brain Catalytic Domain Clinical Data Defect Dementia Development Dietary intake Docking Dose Early treatment Enzymes Flavanol Flavones Functional disorder Funding Genes Genetic Glycogen Synthase Kinases Histologic In Vitro Incidence Intake Lead Modeling Mus Neurofibrillary Tangles Neurons Pathogenicity Pathologic Pathology Pathway interactions Phosphopeptides Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiological Pilot Projects Property Protein Dephosphorylation Protein Tyrosine Kinase Protein Tyrosine Phosphatase Quercetin Reagent Reporting Role Serine Site Specificity Structure Structure-Activity Relationship Study models Test Result Testing Threonine Time Toxic effect Translations Tyrosine Tyrosine Phosphorylation Validation Variant Work acute toxicity age related analog density dietary drug candidate drug market feasibility testing genetic association hyperphosphorylated tau improved in silico in vivo in vivo evaluation innovation insight neuropathology new therapeutic target novel novel strategies off-target site phosphoproteomics positive allosteric modulator prevent receptor tau Proteins tau aggregation tau-1 therapy development

项目摘要

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 GSK3α and GSK3β are prominent tau phosphorylators [19]. GSK3α and GSK3β 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 GSK3α and GSK3β 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) GSK3α and GSK3β 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 GSK3β and GSK3α 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 pYGSK3α and pYGSK3β 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.

项目概要/摘要阿尔茨海默病 (AD) 的致病因素来自遗传学 [1, 2] 和环境影响，包括膳食摄入黄烷醇>黄酮[4-8]。富含过度磷酸化 tau 蛋白的神经原纤维缠结 (NFT) [10] 很突出 AD 神经病理学特征与 AD 痴呆程度密切相关。 [15] [18] 并受到 ApoE 和 PTPRD 基因变异的影响 [3]。改变 tau/NFT 病理生理学的一种方法是减少过度激活的激酶的活性。磷酸化 tau 糖原合酶激酶 GSK3α 和 GSK3β 是重要的 tau 蛋白。 GSK3α 和 GSK3β 通过自身酪氨酸的磷酸化被激活。（pY279 和 pY216）通过已知的酪氨酸激酶 [20] [21, 22] 增加酪氨酸的活性。磷酸酶，使大脑 GSK3α 和 GSK3β 去磷酸化并降低其活性提供了一种减少 AD 中 tau 病理的新方法。证据（在我们第一份 NIA 补充材料的支持下得到了很多发展）现在支持以下角色：a) 受体型蛋白酪氨酸磷酸酶 PTPRD 作为 a) 关键生理磷酸酶磷酸化 (pY) GSK3α 和 GSK3β 和 ii) 减少病理性 AD tau 过度的新靶点磷酸化和 b) 黄烷醇作为先导化合物 PTPRD 正变构调节剂 (PAM) 我们将加强这一证据并朝着这个方向迈进。通过测试假设 a) 增加 GSK3β 的 PTPRD 去磷酸化和 GSK3α 特异性地降低这些 tau 过度磷酸化激酶的活性 PTPRD 与 AD 大脑中 NFT 密度的遗传关联以及 b) 摄入的黄烷醇 AD 发病率随年龄增长而降低 [4-8] 作为 PTPRD 磷酸酶的 PAM，增加 GSK3 具有特异性的去磷酸化，并提供了开发改进的、特异性的途径 PTPRD PAM 可以减少衰老过程中 AD 缺陷的进展。我们将测试这些假设并支持 PTPRD PAM 在多个领域的开发和翻译方法： 1) 我们将通过比较 i: PTPRD 比率来表征 PTPRD 效应的特异性 pYGSK3α 和 pYGSK3β 的去磷酸化和 ii：槲皮素对这些速率的影响与 > 80 种候选神经元 PTPRD 底物中的每一种 3) 我们将合成并测试新型黄烷醇。类似物作为改进的 PTPRD PAM，通过与 PAM 的计算机对接来提名新颖的结构 PTPRD 磷酸酶上的催化位点，在体外测试这些结构，在计算机中完善我们的结构模型并根据这些结果提名/综合/测试新结构。最佳候选正变构调节剂，我们将测试与其他 PTPRD 底物的特异性我们将测试大多数目前上市药物的磷酸肽和脱靶作用位点。 PTPRD PAM 在体内有望产生总体、组织学或行为毒性、生物分布（包括大脑）和目标参与度我们将扩大槲皮素在衰老过程中的作用的验证。 3xTg-AD 小鼠并启动研究以测试该模型中的新型 PTPRD PAM。我们对 AD 病理生理学的理解不断进步，验证了 PTPRD 阳性的新方法变构调节并为开发可以预防和/或治疗 AD 病理生理学的关键方面。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Structure-activity studies of PTPRD phosphatase inhibitors identify a 7-cyclopentymethoxy illudalic acid analog candidate for development.

DOI：
10.1016/j.bcp.2021.114868
发表时间：
2022-01
期刊：
BIOCHEMICAL PHARMACOLOGY
影响因子：
5.8
作者：
Henderson, Ian M.;Zeng, Fanxun;Bhuiyan, Nazmul H.;Luo, Dan;Martinez, Maria;Smoake, Jane;Bi, Fangchao;Perera, Chamani;Johnson, David;Prisinzano, Thomas E.;Wang, Wei;Uhl, George R.
通讯作者：
Uhl, George R.

Substrate-selective positive allosteric modulation of PTPRD's phosphatase by flavonols.

DOI：
10.1016/j.bcp.2022.115109
发表时间：
2022-08
期刊：
BIOCHEMICAL PHARMACOLOGY
影响因子：
5.8
作者：
Henderson, Ian M.;Marez, Carlissa;Dokladny, Karol;Smoake, Jane;Martinez, Maria;Johnson, David;Uhl, George R.
通讯作者：
Uhl, George R.