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

含Tau的神经元包涵体是阿尔茨海默病（AD）和其他具有Tau的病症的突出特征。 tau蛋白病，这意味着细胞清除错误折叠的tau蛋白种类的能力不足，无论是原因还是结果 疾病的过程。Tau是泛素蛋白酶体系统（UPS）的底物，因此阐明了Tau蛋白的生物学活性。 蛋白酶体如何在tau蛋白病中变得功能障碍的机制可能会识别出可能 治疗性地阻止疾病进展。我们最近提供了一个直接的，消极的洞察力， 使用体内和体外模型研究聚集的和寡聚的tau蛋白对蛋白酶体功能的影响。此外，本发明还 我们已经证明，通过cAMP/PKA磷酸化作用，蛋白酶体功能的药理学激活 途径降低病理性tau蛋白水平并挽救认知能力下降。目前，对症治疗 不能阻止疾病的发展。因此，确定 tau蛋白病的最早阶段将有助于开发针对AD的有效疗法。早期 tau蛋白病病症的病理标志是tau蛋白异常错配进入体树突 神经元的间隔。在突触中，积累的tau蛋白被多聚泛素化，这意味着蛋白酶体的缺陷。 介导的蛋白水解，这可能有助于加速突触毒性，因为蛋白酶体在突触毒性中起着不可或缺的作用。 维持突触可塑性和传递的作用。职业发展计划的目标1将 研究错配的突触tau蛋白对突触前和突触后组分中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途径，其由突触内和突触外的神经元调节。 细胞外因子。AIM 2将检验这一假设，即在AD中，PKA的活性下调， 突触蛋白酶体蛋白水解（突触内因子）减少， PACAP（垂体腺苷酸环化酶激活多肽）（突触间因子）。PACAP是一个丰富的 一种神经肽，当从突触前区室释放时，结合并刺激其受体（PAC 1 R）， GPCR亚家族受体位于突触后区室，然后导致cAMP增加 在树突中产生和PKA活化。作为治疗策略，AIM 3将研究PACAP是否 施用恢复PKA活性并激活蛋白酶体功能，导致树突中的tau清除， 改善突触功能最后，AIM 4将利用机器人技术开发一种新的筛查方法 测试蛋白酶体激活剂，并评估突触中受体介导的蛋白水解是否适用于其他 亚家族GPCR。 该奖项期间产生的数据和见解将确定突触后蛋白酶体的机制 这些功能障碍可通过PKA通路失调而导致突触毒性。此外，应用A 受体刺激的蛋白水解的治疗策略，其具有空间限定的作用机制， tau清除可以鉴定一种新的机制来停止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.