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: 10388124
• 负责人: Natura Myeku
• 金额: $ 58.32万
• 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/10388124
• 关键词: 26S proteasome; Address; Adenylate Cyclase; Affect; Alzheimer' s Disease; Alzheimer' s disease therapeutic; Attenuated; Autophagocytosis; Autopsy; Axon; Biochemical; Brain; CREB1 gene; Cell model; Cells; Cognition; Competence; Coupled; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Disease; 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; Interneurons; Lead; Ligands; Liquid substance; Mediating; Memory; Microfluidics; Modeling; Molecular Conformation; Mus; Neurons; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Pharmacology; Phosphorylation; Presynaptic Terminals; Process; Proteins; Proteolysis; Regulation; Role; Seeds; Series; Signal Pathway; Signal Transduction; Synapses; Synaptic Membranes; Synaptic plasticity; System; Tauopathies; Testing; Therapeutic; Toxic effect; Ubiquitin; Vertebral column; attenuation; base; brain tissue; drug market; improved; in vitro Assay; in vivo; model design; multicatalytic endopeptidase complex; nervous system disorder; neural circuit; novel therapeutic intervention; novel therapeutics; 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.

含有 Tau 的神经元包涵体是阿尔茨海默病 (AD) 的一个显着特征，额颞叶 痴呆 (FTD) 和其他 tau 蛋白病疾病，这意味着细胞清除错误折叠 tau 蛋白的能力存在缺陷 物种要么是疾病过程的原因，要么是疾病过程的结果。 Tau 是泛素的底物 蛋白酶体系统 (UPS)，从而阐明蛋白酶体在 tau 蛋白病中如何变得功能失调的机制 可以确定可以作为治疗目标的途径。突触功能障碍，被认为是 AD 和其他 tau 病的早期病理表现与异常错配和 突触中 tau 蛋白的积累。最近的证据表明 AD 突触的致病进展 与突触部分中泛素化蛋白的积累相关，表明 UPS 功能障碍。 在这里，我们提出，突触中错误分类的 tau 蛋白会破坏蛋白酶体活性，从而促进更广泛的突触 毒性。我们假设 tau 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相关的重要通路。 AIM 1 的目标是检查预治疗期间病理性 tau 积累是否存在关系。 和突触后区室、突触蛋白水解功能和 PKA/CREB ​​信号传导状态 使用 AD、FTD 和正常大脑的脑组织。检查 tau 物种的突触分布 突触前和突触后区室及其播种和繁殖的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。努力确定有助于 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 流体隔离突触模型，无论 tau 蛋白聚集在整个细胞还是在突触中 （在跨突触传播期间），由于受损，可能会对 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 Gs 耦合刺激是否有效 GPCR 位于突触末端，可拯救/激活 cAMP/PKA 通路，从而导致增加 突触中 tau 物种的蛋白酶体蛋白水解。受体治疗策略的应用 通过空间明确的作用机制刺激蛋白水解以有效清除 tau 蛋白，可以识别新的 阻止 tau 错配和随后的跨突触扩散的机制。将 GPCR 信号作为目标 激活蛋白酶体介导的蛋白水解的策略可以对寻找新药产生重大影响 蛋白质病。