The role of beta-secretase 1 (BACE1) in modulating excitatory synaptic and circuit function and behavior

β-分泌酶 1 (BACE1) 在调节兴奋性突触和回路功能和行为中的作用

基本信息

批准号：
10607846
负责人：
ANNIE Y YAO
金额：
$ 4.32万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-22 至 2027-02-21
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10607846
关键词：
Address Adult Adverse effects Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease therapeutic Alzheimer&apos s disease therapy Amyloid beta-Protein Behavior Behavioral Behavioral Assay Biochemical Brain Cause of Death Cells Cessation of life Clinical Skills Clinical Trials Cognition Cognitive deficits Communication Data Defect Dementia Development Development Plans Disease Disease Progression Electrophysiology (science)Enzymes Equilibrium Excitatory Synapse Failure Future Generations Genetic Health Hippocampus Human Impaired cognition Impairment Ion Channel Knockout Mice Knowledge Learning Membrane Membrane Potentials Memory Memory Loss Memory impairment Mentors Methods Mus Mutant Strains Mice Neurodegenerative Disorders Neurons Pathologic Patients Peptide Hydrolases Phase Phenotype Physicians Physiological Physiology Play Potassium Property Prosencephalon Publishing Regulation Research Rest Rodent Rodent Model Role Scientist Seizures Senile Plaques Sodium Synapses Synaptic Transmission Synaptic plasticity Technical Expertise Techniques Testing Therapeutic Training Transgenic Organisms abeta accumulation abeta oligomer age related neurodegeneration behavioral study beta-site APP cleaving enzyme 1 career cell type cognitive function designer receptors exclusively activated by designer drugs doctoral student drug development epileptiform excitatory neuron experience extracellular genetic approach genetic manipulation hippocampal pyramidal neuron in vivo inhibitor insight mutant neuronal circuitry neuronal excitability neurophysiology neurotoxicity novel patch clamp presynaptic prevent skills synaptic function therapeutic target voltage

项目摘要

PROJECT SUMMARY Alzheimer’s Disease (AD), the most common cause of dementia, is a debilitating disease that leads to progressive memory loss, cognitive impairment, and ultimately death. Pathological hallmarks of AD include extracellular amyloid beta (Aβ) plaques. β-secretase-1 (β-site APP cleaving enzyme 1, BACE1) is the rate- limiting enzyme of toxic Aβ generation. Transgenic BACE1 KO mouse models of AD led to suppression of AD pathology, which suggests that inhibiting BACE1 may be a rational strategy for AD treatment. However, human clinical trials have shown that BACE1 inhibitors are inefficacious, even worsening cognitive function, among AD patients. This benchtop-to-bedside translational failure is due to our incomplete understanding of BACE1’s physiological function. In particular, the mechanisms underlying neuronal and synaptic impairments in BACE1 deficiency or inhibition is poorly understood. In this proposal, we will address this knowledge gap by testing the hypothesis that BACE1 modulates intrinsic and synaptic neurophysiological properties in a cell-type- and circuit- specific manner in the hippocampus, a major substrate of memory storage derailed by AD. My preliminary data of whole-cell patch clamp of hippocampal pyramidal neurons (PNs) show that selective BACE1 deletion in excitatory neurons leads to neuronal hyperexcitability, suggesting that BACE1 deletion disrupts intrinsic neuronal function in a cell-autonomous manner. Given my preliminary findings, I hypothesize that BACE1 modulates excitability and synaptic transmission in hippocampal PNs by the regulation of ion channels – the identities of which have yet to be fully elucidated. In Aim 1, I will comprehensively determine the ionic basis underlying the hyperexcitability phenotype in my Excitatory-BACE1-KO mice (mice in which BACE1 is selectively deleted in excitatory PNs), and characterize the synaptic transmission and plasticity deficits in Excitatory-BACE1-KO, through patch clamp electrophysiology methods. In Aim 2, I will delineate behavioral deficits Excitatory-BACE1- KO neurons, and rescue hypothesized cognitive deficits in mutant mice by normalizing PN hyperexcitability through a chemogenetic approach. The findings from this study will provide insight into neuronal and synaptic physiology, mechanisms of learning/memory and behavior, and future AD therapeutic strategies. Importantly, completion of this project will help me master current concepts and state-of-the-art techniques in patch clamp electrophysiology, behavior studies, and in vivo genetic perturbation and increase my scientific communication skills through extensive opportunities to present and publish my studies. As an MD/PhD student at UConn Health, I will have access to mentors and experts that will not only directly facilitate my mastery of the necessary technical skills, but I will also have opportunities to continue honing my clinical skills and gain specialized experience during and after my research phase. Fulfilling my training and development plan will be a crucial step toward my future career as a physician-scientist studying the mechanisms underlying neurodegenerative disease in patients.

项目概要阿尔茨海默病 (AD) 是导致痴呆症的最常见原因，是一种使人衰弱的疾病，会导致 AD 的病理特征包括进行性记忆丧失、认知障碍和最终死亡。细胞外淀粉样β (Aβ) 斑块 β-分泌酶-1（β-位点 APP 裂解酶 1，BACE1）是速率- 限制有毒 Aβ 生成的酶导致 AD 的转基因 BACE1 KO 小鼠模型受到抑制。病理学表明，抑制 BACE1 可能是治疗 AD 的合理策略。临床试验表明，BACE1抑制剂对AD患者无效，甚至会恶化认知功能这种从实验室到临床的转化失败是由于我们对 BACE1 的不完全理解。特别是 BACE1 神经和突触损伤的机制。在此提案中，我们将通过测试来解决这一知识差距。假设 BACE1 调节细胞类型和电路中的内在和突触神经生理学特性我的初步数据显示，海马体是记忆存储的主要基质。海马锥体神经元 (PN) 的全细胞膜片钳显示，选择性 BACE1 缺失兴奋性神经元导致神经元过度兴奋，表明 BACE1 缺失破坏了内在神经元根据我的初步发现，我认为 BACE1 可以调节。通过调节离子通道来调节海马 PN 的兴奋性和突触传递 – 的身份在目标1中，我将全面确定其背后的离子基础。我的 Excitatory-BACE1-KO 小鼠（其中 BACE1 在兴奋性 PN），并表征兴奋性-BACE1-KO 中的突触传递和可塑性缺陷，通过膜片钳电生理学方法，在目标 2 中，我将描述兴奋性 BACE1- 行为缺陷。 KO 神经元，并通过使 PN 过度兴奋正常化来挽救突变小鼠的认知缺陷通过化学遗传学方法，这项研究的结果将提供对神经和突触的深入了解。生理学、学习/记忆和行为机制以及未来的 AD 治疗策略。该项目的完成将帮助我掌握膜片钳的当前概念和最先进的技术电生理学、行为研究和体内遗传微扰并增加我的科学交流作为康涅狄格大学健康中心的医学博士/博士生，我通过广泛的机会展示和发表我的研究成果，我将能够接触到导师和专家，他们不仅会直接促进我掌握必要的技术技能，但我也将有机会继续磨练我的临床技能并获得专业经验在我的研究阶段期间和之后完成我的培训和发展计划将是我迈向的关键一步。未来的职业生涯是作为一名医师科学家，研究神经退行性疾病的潜在机制患者。