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Treating neurotoxicity and cognitive deficits due to hyperphosphorylated tau.

治疗由过度磷酸化 tau 引起的神经毒性和认知缺陷。

基本信息

批准号：
10815399
负责人：
Chia-Yi Kuan
金额：
$ 62.88万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-22 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10815399
关键词：
3xTg-AD mouse Alleles Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease patient American Apolipoprotein E Apomorphine Attenuated Axon Axonal Transport Behavioral Biochemical Brain Clinical Treatment Cognitive Cognitive deficits Cryoelectron Microscopy Databases Detergents Disease Dose Estrogen Receptor Modulators Exhibits Exposure to Female Heparin Hippocampus Histologic Impaired cognition Impairment In Situ Nick-End Labeling In Vitro Injections J20 mouse Kinesin Knock-in Mouse Lysosomes Medicine Microtubule-Associated Proteins Mitochondria Mitochondrial Proteins Modeling Movement Mus Mutant Strains Mice Neurites Neurofibrillary Tangles Neurons Osteoporosis prevention Outcome Pathogenesis Pathologic Peptides Phosphorylation Site Physical condensation Pilot Projects Postmenopause Proteins Raloxifene Recombinants Reporter Reporting Respiration Structure Superoxides Symptoms System Testing Therapeutic Toxic effect Toxicity Tests Wild Type Mouse Woman apolipoprotein E-4 biophysical properties cingulate cortex human old age (65+)hyperphosphorylated tau in vivo inhibitor insight male mitochondrial dysfunction neuron loss neuropathology neurotoxic neurotoxicity novel prevent protective effect public health relevance sarkosyl tau Proteins tau aggregation tau interaction tau-1

项目摘要

PROJECT SUMMARY (Description) Hyperphosphorylated tau is the major component of neurofibrillary tangles existing in the brains of Alzheimer’s Disease patients, but whether soluble hyperphosphorylated tau oligomers are already toxic to neurons, and if so, through what mechanisms, have remained unclear. This is largely due to the lack of experimental system to tackle these questions directly. This project will test the hypothesis that hyperphosphorylated tau oligomers promote neurotoxicity before the formation of insoluble tau fibrils, which is amplified by Ab peptides and/or the ApoE4 allele, but either apomorphine and raloxifene treatment mitigates these deleterious effects. This project has three specific aims. Aim 1 will compare the effects of intrahippocampal injection of tau and hyperphosphorylated tau (hyper-ptau) in wildtype and AD-mutant mice (J20 and ApoE KI). We will also compare the onset of behavioral/histological deficit and insoluble tau fibrils in these mice after intrahippocampal injection. Aim 2 will test the effects of hyper-ptau on the viability, mitochondrial functions, and axonal trasnport of cultured neurons. We will also confirm mitochondrial dysfunctions after brain injection of hyper-ptau in vivo. Aim 3 will test the protective effects of apomorphine and raloxifene in preventing hyper-ptau-induced toxicity and cognitive deficits in mice. Both compounds attenuates ptau aggregation in vitro and have a high potential to be repurposed for clinical treatment of AD.

项目概要（描述）过度磷酸化的 tau 蛋白是阿尔茨海默病患者大脑中神经原纤维缠结的主要成分疾病患者，但可溶性过度磷酸化 tau 寡聚体是否已经对神经元有毒，以及是否因此，通过什么机制，目前仍不清楚。这很大程度上是由于缺乏实验系统造成的直接解决这些问题。该项目将检验过度磷酸化 tau 寡聚体的假设在不溶性 tau 原纤维形成之前促进神经毒性，该原纤维通过 Ab 肽和/或 ApoE4 等位基因，但阿扑吗啡和雷洛昔芬治疗均可减轻这些有害影响。这个项目具有三个具体目标。目标 1 将比较海马内注射 tau 蛋白和过度磷酸化 tau 蛋白 (hyper-ptau) 的效果野生型和 AD 突变型小鼠（J20 和 ApoE KI）。我们还将比较行为/组织学缺陷的发生海马内注射后，这些小鼠体内出现不溶性 tau 原纤维。目标 2 将测试 hyper-ptau 对培养细胞的活力、线粒体功能和轴突运输的影响神经元。我们还将在体内脑注射 hyper-ptau 后确认线粒体功能障碍。目标 3 将测试阿扑吗啡和雷洛昔芬预防高 ptau 诱导毒性的保护作用和小鼠的认知缺陷。这两种化合物均可在体外减弱 ptau 聚集，并具有很高的潜力重新用于 AD 的临床治疗。