Receptor-mediated clearance of synaptic tau as a novel therapy for Alzheimer's disease.

含有tau的神经元包涵体是阿尔茨海默病(AD)和其他疾病的显著特征，具有 Tau病，意味着细胞清除错误折叠的tau物种的能力存在缺陷，无论是原因还是结果 疾病的进程。Tau是泛素蛋白酶体系统(UPS)的底物，因此阐明了一种 蛋白酶体如何在肌萎缩侧索硬化症中变得功能失调的机制可能确定 在治疗上有针对性地阻止疾病的进展。我们最近提供了对直接的、负面的 利用体内和体外模型研究聚集型和寡聚型tau对蛋白酶体功能的影响。另外， 我们已经证明，通过cAMP/PKA的磷酸化，蛋白酶体功能的药理学激活 通路降低了病理性tau的水平，挽救了认知能力的下降。目前，对症治疗 在痴呆症阶段不能阻止疾病的发展。因此，确定心绞痛的分子机制 肌松疗法的早期阶段将有助于开发有效的治疗AD的方法。最早的 Tau病的病理特征是tau被错误地分类为躯体树突状细胞 神经元的隔间。在突触中，积累的tau是多泛素化的，这意味着蛋白酶体存在缺陷。 介导的蛋白分解，这可以促进加速的突触毒性，因为蛋白酶体起着不可或缺的作用 在维持突触可塑性和传递方面的作用。职业发展提案的目标1将 研究错位突触tau对突触前和突触后部分蛋白酶体功能的影响。 与突触可塑性相关的途径之一是cAMP/PKA通路，该通路受Intra和PKA的调节 细胞外因素。目标2将检验这一假设，即在AD中，PKA的活性作为一种 突触蛋白酶体蛋白分解减少(突触内因子)的后果，以及 PACAP(垂体腺苷环化酶激活多肽)(突触间因子)。PACAP是一种丰富的 神经肽，当从突触前隔区释放出来时，结合并刺激其受体(PAC1R)，a GPCR亚家族受体位于突触后隔室，从而导致cAMP增加 树突中PKA的产生和活化。作为一种治疗策略，AIM 3将调查PACAP 给药恢复PKA活性并激活蛋白酶体功能，导致树突状细胞和 改善了突触功能。最后，AIM 4将利用机器人技术开发一种新的筛查方法 检测蛋白酶体激活剂，并评估突触中受体介导的蛋白分解是否适用于其他 亚家族GPCR。 在这个奖项中产生的数据和见解将确定突触后蛋白酶体的机制 通过对PKA途径的失调而导致突触毒性的功能障碍。此外，应用一种 受体刺激蛋白降解的治疗策略及其作用机制的空间定位 Tau清除可以确定一种新的机制来阻止tau的错误分类和随后的跨突触扩散。

Tau-containing neuronal inclusions are a prominent feature of Alzheimer’s disease (AD) and other disorders with tauopathy, implying a deficit in the cell’s ability to clear misfolded tau species either as a cause or a consequence of the disease process. Tau is a substrate of the ubiquitin proteasome system (UPS), thus elucidating a mechanism for how proteasome becomes dysfunctional in tauopathy may identify pathways that could be targeted therapeutically to halt disease progression. We have recently provided insight into a direct, negative effect of aggregated and oligomeric tau on proteasome function using in vivo and in vitro models. Additionally, we have shown that pharmacological activation of proteasome function by phosphorylation via cAMP/PKA pathway reduces levels of pathological tau and rescues cognitive decline. Presently, symptomatic treatment during the dementia stage cannot halt the disease progression. Therefore, identifying molecular mechanisms of the earliest stages of tauopathy will help in the development of effective therapies against AD. The early pathological hallmark of tauopathy disorders is abnormal missorting of tau into the somatodendritic compartments of neurons. In synapses, accumulated tau is polyubiquitinated, implying a defect in proteasome- mediated proteolysis, which can contribute to accelerated synaptotoxicity as proteasomes play an indispensable role in maintaining synaptic plasticity and transmission. The Career Development Proposal’s AIM 1 will investigate the effect of missorted synaptic tau on proteasome function in the pre and post -synaptic fractions. One of the pathways related to synaptic plasticity is the cAMP/PKA pathway, which is regulated by the intra and extra -cellular factors. AIM 2 will test the hypothesis that in AD, activity of PKA is downregulated as a consequence of reduced synaptic proteasome proteolysis (the intra-synaptic factor), and depleted levels of PACAP (pituitary adenylate cyclase–activating polypeptide) (the inter-synaptic factor). PACAP is an abundant neuropeptide that when released from pre-synaptic compartments, binds and stimulate its receptor (PAC1R), a GPCR subfamily receptor situated in the postsynaptic compartments which then leads to an increase in cAMP production and PKA activation in dendrites. As a therapeutic strategy, AIM 3 will investigate if PACAP administration restores PKA activity and activates proteasome function leading to tau clearance in dendrites and improved synaptic function. Finally, AIM 4 will make use of robotic technology to develop a new screening assay to test for proteasome activators and to assess if receptor-mediated proteolysis in synapses is applicable to other subfamily GPCRs. The data and insights generated during this award will identify a mechanism of post-synaptic proteasome dysfunction that can contribute to synaptotoxicity by dysregulating the PKA pathway. Moreover, application of a therapeutic strategy of receptor-stimulated proteolysis with spatially defined mechanism of action for effective tau clearance can identify a new mechanism to halt missorting of tau and subsequent trans-synaptic spread.