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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（说明）过度磷酸化的tau蛋白是阿尔茨海默病患者脑内神经元缠结的主要成分疾病患者，但是否可溶性过度磷酸化tau寡聚体已经对神经元有毒，如果那么通过什么机制呢，目前还不清楚。这在很大程度上是由于缺乏实验系统直接解决这些问题。这个项目将测试过度磷酸化的tau寡聚体在形成不溶性tau原纤维之前促进神经毒性，所述不溶性tau原纤维被Ab肽和/或所述tau蛋白放大。 ApoE 4等位基因，但阿扑吗啡和雷洛昔芬治疗减轻这些有害作用。这个项目有三个具体目标。目的1将比较海马内注射tau蛋白和过度磷酸化tau蛋白（hyper-ptau）对海马神经元的影响。野生型和AD突变小鼠（J20和ApoE KI）。我们还将比较行为/组织学缺陷的发生，以及海马内注射后这些小鼠中的不溶性tau纤维。目的2：检测hyper-ptau对体外培养的大鼠海马神经元细胞活力、线粒体功能和轴突转运的影响。神经元我们还将在体内证实脑注射hyper-ptau后的线粒体功能障碍。目的3将测试阿扑吗啡和雷洛昔芬在预防高ptau诱导的毒性中的保护作用和认知缺陷。这两种化合物在体外减弱ptau聚集，用于AD的临床治疗。