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的神经元包涵体是阿尔茨海默病（AD）的突出特征，额颞叶神经元包涵体是阿尔茨海默病（AD）的主要特征。 痴呆症（FTD）和其他tau蛋白病疾病，这意味着细胞清除错误折叠的tau蛋白的能力不足 这是一种疾病的原因或后果。Tau是泛素的底物， 蛋白酶体系统（UPS），从而阐明了蛋白酶体在tau蛋白病中功能失调的机制 可以识别出治疗靶向的途径。突触功能障碍，这被认为是一个 AD和其他Tau蛋白病的早期病理表现与异常分类错误有关， 突触中tau的积累。最近的证据表明，AD中突触的致病进展 与突触组分中泛素化蛋白的积累相关，提示UPS功能障碍。 在这里，我们提出，突触中的错配tau蛋白破坏了蛋白酶体的活性，有助于更广泛的突触。 毒性我们假设tau蛋白诱导的突触蛋白水解受损的后果之一是持续的， PKA全酶的四聚体（无活性）构象和CREB转录信号的下调， 与突触可塑性和记忆有关的重要通路。 AIM 1的目的是检查是否有病理性tau蛋白的积累之间的关系， 和突触后区室，突触蛋白水解的功能和PKA/CREB信号的状态 使用AD、FTD和正常大脑的脑组织。在脑组织中tau种类的突触分布的检查 突触前和突触后区室及其种子和繁殖能力将使我们能够识别 两种tau蛋白病中突触tau蛋白的生化特征。为了努力确定有助于实现以下目标的机制， 突触毒性，AIM 2将在一系列体外试验中使用原代神经元和基于微流体的细胞 流体隔离突触的模型，无论是tau聚集体在整个细胞中还是在突触中的积累 （在跨突触传播期间），由于受损的细胞内信号传导，可能对PKA/CREB信号传导产生负面影响。 蛋白酶体清除机制作为一种治疗策略，AIM 3将研究刺激GS偶联的 位于突触末梢的GPCR拯救/激活cAMP/PKA通路，导致增加的 突触中tau种类的蛋白酶体蛋白水解。应用受体介导的治疗策略- 具有空间上确定的有效tau清除作用机制的刺激蛋白水解，可以鉴定新的 阻止tau的错误分类和随后的跨突触扩散的机制。靶向GPCR信号传导作为 激活蛋白酶体介导蛋白水解的策略在发现用于 蛋白质病