DOES A SHIFT FROM 4R TO 3R TAU PROJECT AGAINST AMYLOID BETA-INDUCED COGNITIVE DEF

从 4R 到 3R TAU 项目的转变是否可以对抗淀粉样蛋白 Beta 引起的认知缺陷

• 批准号: 8685859
• 负责人: TIMOTHY M. MILLER
• 金额: $ 19万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8685859
• 关键词: Address; Adult; Affect; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Animal Model; Animals; Antisense Oligonucleotides; Behavioral; Bicuculline; Biochemistry; Biological Assay; Clinic; Cognitive; Cognitive deficits; Data; Dementia; Deposition; Dose; Employee Strikes; Frontotemporal Dementia; Functional disorder; GABA Antagonists; Grant; Hippocampus (Brain); Human; Immunohistochemistry; Infusion procedures; Knock-out; Knockout Mice; Learning; Measures; Memory; Messenger RNA; Modeling; Molecular; Mus; Neuraxis; Neurodegenerative Disorders; Pathogenesis; Pathology; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Phase I Clinical Trials; Picrotoxin; Positioning Attribute; Progressive Supranuclear Palsy; Protein Isoforms; Proteins; RNA Splicing; Role; Seizures; Slice; Staining method; Stains; Synapses; Technology; Testing; Therapeutic; Translating; cognitive change; experience; improved; in vivo; insight; mature animal; neuronal excitability; novel strategies; novel therapeutics; prevent; protective effect; public health relevance; research study; response; tau Proteins; tau aggregation; tool

DESCRIPTION (provided by applicant): Alzheimer's Disease (AD), the most common form of dementia, is characterized by two pathological hallmarks: tau neurofibrillary tangles (NFT) and amyloid-¿ (A¿) plaques. As an alternative approach to current A¿-targeted therapies, we propose to focus on tau. Several groups have shown that mice lacking endogenous tau, when crossed to A¿ depositing hAPP mice, show a significant increase in learning/memory performance and are protected from chemically induced seizures. Our preliminary data show that, as predicted from the tau knockout, lowering total tau protects against seizures. Surprisingly, we also have found that converting the 4R tau isoform to 3R tau without changing total tau also protects against seizures. We now propose to determine whether converting 4R tau to 3R will protect against amyloid beta induced cognitive deficits in PSAPP mice. In addition, using measures of neuronal excitability in response to GABA antagonists, we will correlated the amount of tau knockdown and shift from 4R to 3R with the change in neuronal excitability. Using immunohistochemical and biochemistry, we test whether changing tau isoforms changes tau localization or the components of the synapse. The antisense oligonucleotide approach used in this grant to modify tau has been used successfully in a Phase I clinical trial for patients with ALS. Thus, demonstrating a therapeutic benefit using oligos that change 4R to 3R in mice may be readily translatable to human.

描述（由申请人提供）：阿尔茨海默病（AD）是最常见的痴呆形式，其特征在于两个病理标志：tau 神经原纤维缠结（NFT）和淀粉样蛋白（A）斑块。作为当前 A¿ 靶向疗法的替代方法，我们建议重点关注 tau 蛋白。几个研究小组已经表明，缺乏内源性 tau 蛋白的小鼠在与 A 沉积 hAPP 小鼠杂交时，学习/记忆性能显着提高，并且免受化学诱导的癫痫发作。我们的初步数据表明，正如 tau 基因敲除所预测的那样，降低总 tau 蛋白可以预防癫痫发作。令人惊讶的是，我们还发现，在不改变总 tau 蛋白的情况下将 4R tau 异构体转化为 3R tau 蛋白也能预防癫痫发作。我们现在建议确定将 4R tau 转化为 3R 是否可以防止 PSAPP 小鼠中淀粉样蛋白 β 诱导的认知缺陷。此外，利用对 GABA 拮抗剂反应的神经元兴奋性测量，我们将 tau 蛋白敲低量和从 4R 到 3R 的转变与神经元兴奋性的变化相关联。使用免疫组织化学和生物化学，我们测试改变 tau 亚型是否会改变 tau 定位或突触的组成。本次资助中用于修饰 tau 的反义寡核苷酸方法已成功用于 ALS 患者的 I 期临床试验。因此，证明使用将小鼠中的 4R 变为 3R 的寡核苷酸的治疗益处可能很容易转化为人类。