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: 10710182
• 负责人: Anne Goettemoeller
• 金额: $ 4.77万
• 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/10710182
• 关键词: Acceleration; Action Potentials; 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; Genetic; Human; Image; Interneurons; Intervention; Knock-in Mouse; Knowledge; Label; Laboratory Finding; 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; SCN1A protein; 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.

项目摘要 阿尔茨海默氏病（AD）是最普遍的痴呆形式，导致神经元突触（脊柱）损失，大脑 萎缩和最终记忆丧失。尽管预计广告将从受影响的美国人的580万增长到13.8 到2050年，百万富翁还没有有效的预防治疗。广告研究主要专注于治疗 病理淀粉样蛋白斑块和tau缠结。但是，最近的研究表明斑块和叮叮当当 病理在疾病中相对较晚。对AD患者和疾病模型的最新研究已放置 在淀粉样β斑块病理学之前，过度兴奋，增加了锥体神经输血，提供早期 疾病干预点。锥体神经元过度兴奋性是一种现象，可以由 抑制/兴奋性输入的不平衡。因此，最近的文献表明了独特的中间神经元 在小鼠模型中，在这种早期疾病状态下，亚型被破坏，特别是快速刺激性的白蛋白（FS-） PV）中间神经元。 FS-PV中间神经元在牙菌斑前阶段显示动作电位变化 AD小鼠模型中的病理学，导致锥体神经元过度兴奋。众所周知，发射模式 FS-PV中间神经元可以通过特异性的表达或生物物理特性的变化来改变 电压门控通道（VGC）。该提案旨在确定1。改变的机械基础 FS-PV Interneuron发射和2。 过度兴奋和相关的脊柱损失。在AIM 1中，我预测Pre-Plaque AD中的FS-PV射击发生了变化是 由VGC的生物物理变化引起。为了评估这些潜在变化，我将使用电生理学 测量VGC生物物理变化的方法。我还将用野生型和广告隔离实时FS-PV中间神经元 评估VGC mRNA表达的小鼠模型变化。在AIM 2中，我预测FS-PV的恢复射击 平面AD中的中间神经元将防止锥体神经元过度刺激性和相关的脊柱丧失。在这个 AIM，将使用两种方法来实现FS-PV中间神经元的恢复触发：化学遗传学和细胞 - 类型特异性基因疗法。将评估锥体神经元过度兴奋性和形态（脊柱丧失） 使用贴片钳电生理学和两光子成像。该提案的结果将提供早期 AD干预的点和具有神经退行性预防潜力的可翻译治疗方法。