Effect of SHIFT FROM 4R TO 3R TAU on AMYLOID BETA-INDUCED COGNITIVE DEFICITS

从 4R TAU 转变为 3R TAU 对淀粉样蛋白诱发的认知缺陷的影响

基本信息

批准号：
8492321
负责人：
TIMOTHY M. MILLER
金额：
$ 22.8万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8492321
关键词：
Address Adult Affect Alzheimer&apos 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

项目摘要

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）：阿尔茨海默氏病 (AD) 是最常见的痴呆症，具有两个病理特征：tau 神经原纤维缠结 (NFT) 和淀粉样蛋白-¿ (A¿) 斑块作为当前 A¿ 的替代方法。 - 靶向治疗，我们建议重点关注 tau 蛋白，几个研究小组已经表明，当与 A¿ 杂交时，小鼠缺乏内源性 tau 蛋白。我们的初步数据表明，正如 tau 敲除所预测的那样，降低总 tau 可以防止癫痫发作。在不改变总 tau 的情况下，将 4R tau 异构体转化为 3R tau 也可以预防癫痫发作。我们现在建议确定将 4R tau 转化为 3R 是否可以预防癫痫发作。此外，通过测量对 GABA 拮抗剂的神经元兴奋性，我们将使用免疫组织化学和生物化学将 tau 蛋白敲低和从 4R 到 3R 的转变与神经元兴奋性的变化相关联。我们测试改变 tau 异构体是否会改变 tau 定位或突触成分。本次资助中用于修饰 tau 的反义寡核苷酸方法具有以下特点：已成功用于 ALS 患者的 I 期临床试验，因此，证明使用将 4R 改变为 3R 的寡核苷酸在小鼠中的治疗益处可能很容易转化为人类。