The Role of Synaptic Proteolysis in Alzheimer's Disease and Therapeutic Implications

突触蛋白水解在阿尔茨海默病中的作用及其治疗意义

• 批准号: 10621813
• 负责人: Natura Myeku
• 金额: $ 56.38万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10621813
• 关键词: 26S proteasome; Adenylate Cyclase; Affect; Alzheimer' s Disease; Alzheimer' s disease patient; Attenuated; Autophagocytosis; Autopsy; Axon; Biochemical; Brain; CREB1 gene; Cell model; Cells; Cognition; Competence; Coupled; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Disease; Disease Progression; Down-Regulation; Drug Targeting; Event; Frontotemporal Dementia; Functional disorder; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Genetic Transcription; Goals; Holoenzymes; Impaired cognition; Impairment; Ligands; Mediating; Memory; Microfluidics; Modeling; Molecular Conformation; Mus; Neurons; Pathogenicity; Pathologic; Pathology; Pathway interactions; Phosphorylation; Presynaptic Terminals; Process; Proteins; Proteolysis; Regulation; Role; Series; Signal Pathway; Signal Transduction; Synapses; Synaptic Membranes; Synaptic plasticity; System; Tauopathies; Testing; Therapeutic; Toxic effect; Ubiquitin; Vertebral column; attenuation; brain tissue; drug market; improved; in vitro Assay; in vivo; model design; monomer; multicatalytic endopeptidase complex; nervous system disorder; neural circuit; novel therapeutic intervention; novel therapeutics; pharmacologic; postsynaptic; presynaptic; protein degradation; protein oligomer; proteostasis; receptor; synaptic function; targeted treatment; tau Proteins; tau aggregation

Tau-containing neuronal inclusions are a prominent feature of Alzheimer’s disease (AD), frontal temporal dementia (FTD) 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 mechanisms how proteasome becomes dysfunctional in tauopathy may identify pathways that could be targeted therapeutically. Synaptic dysfunction, which is thought to be an early pathological manifestation in AD and other tauopathies, is associated with abnormal missorting and accumulation of tau in synapses. And recent evidence suggests that pathogenic progression in synapses in AD correlates with accumulation of ubiquitinated proteins in synaptic fractions, suggesting UPS dysfunction. Here we propose that missorted tau in synapses disrupts proteasomal activity contributing to broader synaptic toxicity. We hypothesize that one of the consequences of tau-induced impaired synaptic proteolysis is sustained tetrameric (inactive) conformation of PKA holoenzyme and downregulation of CREB transcription signaling, an important pathway related to synaptic plasticity and memory. The goal of AIM 1 is to examine whether there is a relationship between accumulation of pathological tau in pre and post -synaptic compartments, the function of synaptic proteolysis and the status of PKA/CREB signaling using brain tissue from AD, FTD and normal brains. Examination of the synaptic distribution of tau species in the pre and post synaptic compartment and its competency to seed and propagate will enable us to identify the biochemical signature of synaptic tau in two tauopathies. In an effort to identify mechanisms that contribute to synaptic toxicity, AIM 2 will test in a series of in vitro assays using primary neurons and microfluidic-based cell model of fluidically isolated synapses, whether accumulation of tau aggregates throughout the cell or in synapses (during trans-synaptic propagation), can elicit a negative effect on the PKA/CREB signaling due to impaired proteasome clearance mechanism. As a therapeutic strategy, AIM 3 will investigate if stimulation of Gs-coupled GPCR, situated on the synaptic terminals, rescues/activates cAMP/PKA pathway leading to increased proteasome proteolysis of tau species in synapses. The 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. Targeting GPCR signaling as a strategy to activate proteasome mediated proteolysis can have a significant impact in finding new drugs for proteinopathy diseases.

含tau的神经元夹杂物是阿尔茨海默氏病（AD），额叶临时的重要特征 痴呆症（FTD）和其他带有tauopathy的疾病，这意味着该细胞清除错误折叠的tau的能力 物种是疾病过程的原因或结果。 tau是泛素的底物 蛋白酶体系统（UPS），因此阐明了蛋白酶体在tauopathy中的功能失调 可以识别可以热靶向的途径。突触功能障碍，被认为是 AD和其他tauopathies中的早期病理表现与异常缺失和 tau在突触中的积累。最近的证据表明，AD突触的致病性进展 与突触级分中泛素化蛋白的积累相关，表明功能障碍。 在这里，我们提出，在突触中将tau丢弃会破坏有助于更广泛突触的蛋白酶体活动 毒性。我们假设tau诱导的突触蛋白水解的后果之一是持续的 PKA全酶的四聚体构象和CREB转录信号的下调，一个 与合成可塑性和记忆有关的重要途径。 目标1的目的是检查病理tau的积累之间是否存在关系 和突触后室，突触蛋白水解的功能以及PKA/CREB信号的状态 使用AD，FTD和正常大脑的脑组织。检查tau物种的突触分布 前后突触室及其播种和传播的能力将使我们能够确定 两种tauopath中突触tau的生化特征。为了确定有助于 突触毒性，AIM 2将使用原代神经元和基于微流体的细胞进行一系列体外测定测试 流体隔离的突触模型，无论是在整个细胞中的tau聚集物的积累还是在突触中 （在反式突触传播期间），可能会对由于受损而引起的PKA/CREB信号产生负面影响 蛋白酶体清除机制。作为治疗策略，AIM 3将调查GS耦合的刺激是否 GPCR位于突触终端上，营救/激活CAMP/PKA途径，导致增加 突触中tau物种的蛋白酶体蛋白水解。应用受体治疗策略 通过空间定义的有效tau清除的作用机理刺激蛋白水解，可以识别一个新的 阻止tau的机制和随后的反式突触扩散。将GPCR信号作为一个 激活蛋白酶体介导的蛋白水解的策略可能会对寻找新药物产生重大影响 蛋白质疾病。