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.

项目摘要/摘要阿尔茨海默氏病（AD）从遗传学[1，2]获得致病性贡献，并从环境影响，包括黄烷醇>黄酮的饮食摄入量[4-8]。富含高磷酸化的tau蛋白的神经原纤维缠结（NFTS）是突出的 AD神经病理学的特征。 NFT密度与AD痴呆程度很好地相关 [15] [18]，受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激酶的活性磷酸化tau。糖原合酶激酶GSK3α和GSK3β是突出的tau 磷酸化剂[19]。 GSK3α和GSK3β通过其自身酪氨酸的磷酸化激活（PY279和PY216）通过已知的酪氨酸激酶[20] [21，22]。酪氨酸的活性增加磷酸酶（S）脱磷酸化并减少脑GSK3α和GSK3β的活性提供了一种新的方法来减少AD中的Tau病理学。证据（在我们的第一个NIA补充剂的支持下得到了很多支持）现在支持以下角色：a）受体类型蛋白酪氨酸磷酸酶PTPRD作为A I）关键生理磷酸酶对于磷酸（PY）GSK3α和GSK3β和II）降低病理学和磷酸化和b）黄烷醇作为铅复合PTPRD阳性变构调节剂（PAMS）这增加了所需的PTPRD活动。我们将增强这一证据并朝着通过测试假设的翻译，即a）增加了GSK3β和 GSK3α降低了这些特异性的这些tau-hyperphosphopphosphoryplosphorating激酶的活性 PTPRD在ad脑中的NFT密度与摄入量的黄烷醇的遗传关联降低衰老[4-8]的AD发病率是PTPRD磷酸酶的PAM，增加GSK3 具有特异性的去磷酸化，并为开发改进，特定的途径提供了途径 PTPRD可以减少在衰老期间定义AD的进展。我们将测试这些假设并支持PTPRD PAM的开发和翻译方法：1）我们将通过比较I：PTPRD的速率来表征PTPRD效应的特异性 pygsk3α和pygsk3β和ii的去磷酸化对这些速率的影响与槲皮素的影响 > 80个候选神经元PTPRD底物中的每一个。 3）我们将合成并测试新颖的黄酮类似物作为改进的PTPRD PAM，通过在PAM与PAM与PAM对接中提名新结构 PTPRD磷酸酶的催化位点，在体外测试这些结构，在计算机中精炼我们基于这些结果，模型和提名/合成/测试新结构。为了最佳候选阳性变构调节器，我们将测试规格与其他PTPRD底物当前销售药物的磷酸肽和脱离目标的作用部位。我们将测试最多有希望的PTPRD PAM在体内用于总体组织学或行为毒性，生物分布（包括大脑）和目标参与。我们将扩大槲皮素效应在衰老中的验证 3XTG-AD小鼠并开始研究该模型中的新型PTPRD PAM。这项工作将促进我们对AD病理生理学的理解，验证新的PTPRD阳性方法变构调节，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.