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

描述（由申请人提供）：阿尔茨海默病（AD）是最常见的痴呆症形式，其特点是两种病理标志：tau神经原纤维缠结（NFT）和淀粉样蛋白-¿（A¿）斑块。作为目前A -靶向治疗的替代方法，我们建议关注tau。一些研究小组已经证明，缺乏内源性tau蛋白的小鼠与A -沉积hAPP小鼠杂交后，学习/记忆能力显著提高，并且免受化学诱发癫痫的影响。我们的初步数据显示，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亚型转化为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是否会保护papp小鼠免受淀粉样蛋白诱导的认知缺陷。此外，通过测量神经元兴奋性对GABA拮抗剂的反应，我们将tau蛋白敲低的数量和从4R到3R的移位与神经元兴奋性的变化联系起来。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定位或突触成分。这项拨款中使用的修饰tau蛋白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，利用在小鼠中改变4R到3R的寡核苷酸证明治疗益处可能很容易转化为人类。

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.