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

受体介导的突触 tau 蛋白清除作为阿尔茨海默病的新疗法。

• 批准号: 9913433
• 负责人: Natura Myeku
• 金额: $ 12.46万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9913433
• 关键词: Activities of Daily Living; Acute; Address; Affinity; Age; Agonist; Alzheimer' s Disease; Alzheimer' s disease therapy; Attenuated; Autophagocytosis; Award; Binding; Biochemical; Biological Assay; Brain; CREB1 gene; Cells; Competence; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cytosol; Data; Defect; Dementia; Dendrites; Development; Disease; Disease Progression; Down-Regulation; Drug Screening; Excision; Functional disorder; Future; G-Protein-Coupled Receptors; Holoenzymes; Impaired cognition; Impairment; Lead; Mediating; Memory; Molecular; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Neuropeptides; Neurotransmitters; PACAPR-1 protein; Pathogenesis; Pathologic; Pathology; Pathway interactions; Peptides; Pharmacology; Phosphorylation; Phosphotransferases; Play; Process; Production; Proteins; Proteolysis; Reporter; Research; Robotics; Role; Signal Pathway; Signal Transduction; Slice; Stains; Synapses; Synaptic Transmission; Synaptic plasticity; System; Tauopathies; Technology; Testing; Therapeutic; Training; Ubiquitin; calmodulin-dependent protein kinase II; career development; drug discovery; effective therapy; extracellular; functional status; improved; in vitro Model; in vivo; insight; misfolded protein; multicatalytic endopeptidase complex; novel therapeutics; pituitary adenylate cyclase activating polypeptide; postsynaptic; protein degradation; receptor; robotic microscopy; screening; serial imaging; symptom treatment; synaptic function; targeted treatment; tau Proteins; tau aggregation; tool

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.

含有 Tau 的神经元包涵体是阿尔茨海默病 (AD) 和其他疾病的一个显着特征 tau蛋白病，意味着细胞清除错误折叠的tau蛋白的能力缺陷，无论是原因还是结果 的疾病过程。 Tau 是泛素蛋白酶体系统 (UPS) 的底物，因此阐明了 tau蛋白病中蛋白酶体如何变得功能失调的机制可能会确定可能的途径 针对性治疗以阻止疾病进展。我们最近提供了对直接的、负面的洞察 使用体内和体外模型研究聚集和寡聚 tau 对蛋白酶体功能的影响。此外， 我们已经证明，通过 cAMP/PKA 磷酸化可药理激活蛋白酶体功能 途径可降低病理性 tau 蛋白水平并挽救认知能力下降。目前，对症治疗 在痴呆症阶段无法阻止疾病的进展。因此，确定其分子机制 tau蛋白病的最早阶段将有助于开发针对AD的有效疗法。早期的 tau 蛋白病的病理特征是 tau 蛋白异常错误分选到体细胞树突中 神经元区室。在突触中，积累的 tau 蛋白被多泛素化，这意味着蛋白酶体存在缺陷 介导的蛋白水解作用，这可能有助于加速突触毒性，因为蛋白酶体发挥着不可或缺的作用 维持突触可塑性和传递的作用。职业发展提案的 AIM 1 将 研究错配的突触 tau 对突触前和突触后部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，该途径受突触内和突触可塑性的调节。 细胞外因素。 AIM 2 将检验这样的假设：在 AD 中，PKA 的活性下调作为一种 突触蛋白酶体蛋白水解作用（突触内因子）减少以及 PACAP（垂体腺苷酸环化酶激活多肽）（突触间因子）。 PACAP 是一种丰富的 当从突触前区室释放时，结合并刺激其受体 (PAC1R) 的神经肽， GPCR 亚家族受体位于突触后区室，导致 cAMP 增加 树突中 PKA 的产生和激活。作为一种治疗策略，AIM 3 将研究 PACAP 是否 给药可恢复 PKA 活性并激活蛋白酶体功能，从而导致树突中 tau 蛋白的清除， 改善突触功能。最后，AIM 4 将利用机器人技术开发新的筛选方法 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 GPCR 亚科。 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 功能障碍可通过 PKA 通路失调导致突触毒性。此外，应用一个 受体刺激蛋白水解的治疗策略，具有空间明确的作用机制，可有效 tau 清除可以找到一种新机制来阻止 tau 错配和随后的跨突触扩散。