Mechanism and restoration of altered firing in interneurons during early phase Alzheimer's Disease

阿尔茨海默病早期中间神经元放电改变的机制和恢复

• 批准号: 10537621
• 负责人: Anne Goettemoeller
• 金额: $ 4.68万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10537621
• 关键词: Action Potentials; Address; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; American; Biophysical Process; Biophysics; Cells; Data; Dementia; Disease; Disease model; Electrophysiology (science); Enhancers; Faculty; Family; Frequencies; Functional disorder; Gene Expression; Human; Image; Interneurons; Intervention; Knock-in Mouse; Knowledge; Label; Literature; Manuals; Measures; Memory Loss; Methods; Modeling; Molecular; Morphology; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Neurosciences; Parvalbumins; Patch-Clamp Techniques; Pathologic; Pathology; Pattern; Phase; Phenotype; Prevention; Preventive treatment; Process; Reporting; Research; Senile Plaques; Somatosensory Cortex; Sorbus; Synapses; Therapeutic; Time; Universities; Vertebral column; Viral; Work; biophysical properties; cell type; cerebral atrophy; designer receptors exclusively activated by designer drugs; early detection biomarkers; educational atmosphere; entorhinal cortex; excitatory neuron; excitotoxicity; familial Alzheimer disease; gene therapy; hippocampal pyramidal neuron; in vivo; mRNA Expression; member; mouse model; novel; novel diagnostics; novel therapeutics; overexpression; patch clamp; prevent; prodromal Alzheimer' s disease; programs; restoration; tau Proteins; therapeutically effective; two photon microscopy; two-photon; voltage gated channel

PROJECT SUMMARY Alzheimer’s Disease (AD) is the most prevalent form of dementia, causing neuronal synapse (spine) loss, brain atrophy, and eventual memory loss. Although AD is expected to grow from 5.8 million affected Americans to 13.8 million by 2050, there remains no effective preventative treatment. AD research has primarily focused on treating pathological amyloid-beta plaques and tau tangles. However, recent research suggests plaque-and-tangle pathology occurs relatively late in the disease. Recent studies in AD patients and models of disease have placed hyperexcitability, increased pyramidal neuron firing, prior to amyloid-beta plaque pathology, providing an early point for disease intervention. Pyramidal neuron hyperexcitability is a phenomenon that can result from an imbalance of inhibitory/excitatory inputs. Recent literature has shown accordingly that distinct interneuron subtypes are disrupted at this early disease state in mouse models, specifically fast-spiking parvalbumin (FS- PV) interneurons. FS-PV interneurons display altered action potential firing in the prodromal phase of plaque pathology in AD mouse models, resulting in pyramidal neuron hyperexcitability. It is known that firing patterns of FS-PV interneurons can be altered through changes in the expression or biophysical properties of specific voltage-gated channels (VGCs). This proposal seeks to determine 1. Mechanistic underpinnings of altered FS-PV interneuron firing, and 2. If restored firing is successful in preventing pyramidal neuron hyperexcitability and associated spine loss. In Aim 1, I predict altered FS-PV firing in pre-plaque AD is caused by biophysical changes in VGCs. To assess these potential changes, I will use electrophysiological methods to measure VGC biophysical changes. I will also isolate live FS-PV interneurons from wild-type and AD mouse models to assess VGC mRNA expression changes. In Aim 2, I predict restored firing of FS-PV interneurons in pre-plaque AD will prevent pyramidal neuron hyperexcitability and associated spine loss. In this aim, restored firing of FS-PV interneurons will be achieved using two approaches: chemogenetics and a cell- type-specific gene therapy. Pyramidal neuron hyperexcitability and morphology (spine loss) will be assessed using patch-clamp electrophysiology and two-photon imaging. The results of this proposal will provide an early point for AD intervention and a translatable therapeutic method with potential for neurodegeneration prevention.

项目概要 阿尔茨海默病 (AD) 是最常见的痴呆症，会导致神经元突触（脊柱）丧失、大脑 尽管 AD 患者预计将从 580 万增加到 13.8 万人。 到 2050 年，仍然没有有效的预防性治疗方法，AD 研究主要集中在治疗上。 病理性β淀粉样蛋白斑块和tau蛋白缠结然而，最近的研究表明斑块和缠结。 最近对 AD 患者和疾病模型的研究表明，该疾病的病理学发生相对较晚。 过度兴奋，锥体神经元放电增加，在淀粉样β斑块病理发生之前，提供了早期诊断 锥体神经元过度兴奋是一种可能导致疾病干预的现象。 抑制性/兴奋性输入的不平衡相应地表明了不同的中间神经元。 在小鼠模型中，亚型在这种早期疾病状态下被破坏，特别是快速尖峰小清蛋白（FS- PV）中间神经元在斑块的前驱期显示出改变的动作电位放电。 AD 小鼠模型中的病理学，导致锥体神经过度兴奋。 FS-PV 中间神经元可以通过改变特定神经元的表达或生物物理特性来改变。 该提案旨在确定 1. 改变的机制基础。 FS-PV 中间神经元放电，以及 2. 恢复放电是否成功阻止锥体神经元 在目标 1 中，我预测斑块前 AD 中 FS-PV 放电的改变是。 为了评估这些潜在的变化，我将使用电生理学方法。 我还将从野生型和 AD 中分离出活的 FS-PV 中间神经元。 评估 VGC mRNA 表达变化的小鼠模型 在目标 2 中，我预测 FS-PV 的放电会恢复。 AD 斑块前的中间神经元将预防神经元过度兴奋和相关的脊柱损失。 为了实现这一目标，FS-PV 中间神经元的恢复放电将通过两种方法来实现：化学遗传学和细胞- 将评估锥体神经元过度兴奋性和形态（脊柱损失）。 使用膜片钳电生理学和双光子成像，该提案的结果将提供早期的结果。 AD 干预的重点和具有预防神经退行性变潜力的可转化治疗方法。