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

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神经元缠结（NFT）和淀粉样蛋白（A）斑块。作为目前A靶向治疗的替代方法，我们建议将重点放在tau上。几个研究小组已经表明，缺乏内源性tau蛋白的小鼠，当与A？沉积hAPP小鼠杂交时，显示出学习/记忆表现的显著增加，并且受到保护免于化学诱导的癫痫发作。我们的初步数据显示，正如从tau敲除预测的那样，降低总tau可以防止癫痫发作。令人惊讶的是，我们还发现，将4 R tau亚型转化为3R tau而不改变总tau也可以防止癫痫发作。我们现在建议确定将4 R tau转化为3R是否会保护PSAPP小鼠免受淀粉样蛋白β诱导的认知缺陷。此外，使用响应于GABA拮抗剂的神经元兴奋性的测量，我们将tau敲低的量和从4 R到3R的移位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，我们测试是否改变tau亚型改变tau定位或突触的组成部分。在这项授权中使用的修饰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，使用在小鼠中将4 R改变为3R的寡核苷酸证明治疗益处可以容易地转化为人类。

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.