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

描述(申请人提供)：阿尔茨海默病(AD)是痴呆症最常见的形式，以两个病理特征为特征：tau神经原纤维缠结(NFT)和淀粉样蛋白(A)斑块。作为当前A？靶向治疗的另一种方法，我们建议专注于tau。几个小组已经表明，缺乏内源性tau的小鼠，当与A？沉积Happ的小鼠杂交时，表现出显著的学习/记忆能力提高，并免受化学诱导的癫痫发作。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可以防止癫痫发作。令人惊讶的是，我们还发现，在不改变总tau的情况下将4R tau亚型转换为3R tau也可以预防癫痫发作。我们现在建议确定将4R tau转换为3R是否可以预防淀粉样β蛋白诱导的PSAPP小鼠的认知障碍。此外，使用对GABA拮抗剂反应的神经元兴奋性的测量，我们将把tau基因敲除的量和从4R到3R的量与神经元兴奋性的变化联系起来。利用免疫组织化学和生物化学方法，我们检验改变tau亚型是否会改变tau的定位或突触的成分。这项授权中用来修饰tau的反义寡核苷酸方法已经成功地用于ALS患者的I期临床试验。因此，在小鼠身上使用将4R改变为3R的寡核苷酸来展示治疗益处可能很容易翻译给人类。

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.