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

项目摘要 阿尔茨海默氏病（AD）是痴呆的最普遍形式，其引起神经元突触（脊柱）丧失、脑损害、神经元损伤和神经元损伤。 萎缩最终导致记忆丧失尽管AD预计将从580万受影响的美国人增长到1380万， 到2050年，仍然没有有效的预防性治疗。AD研究主要集中在治疗 病理性β淀粉样蛋白斑和tau蛋白缠结。然而，最近的研究表明， 病理学在疾病中相对较晚发生。最近在AD患者和疾病模型中的研究表明， 在β淀粉样蛋白斑块病理学之前，过度兴奋，锥体神经元放电增加， 进行疾病干预。锥体神经元过度兴奋是一种现象，可能是由于 抑制性/兴奋性输入的不平衡。最近的文献相应地表明，不同的中间神经元 在小鼠模型中，在这种早期疾病状态下亚型被破坏，特别是快速尖峰小清蛋白（FS- PV）中间神经元。FS-PV中间神经元在斑块前驱期显示改变的动作电位放电 在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， FS-PV中间神经元可以通过改变特定蛋白的表达或生物物理性质来改变。 电压门控通道（VGC）。该提案旨在确定1。改变的机制基础 FS-PV中间神经元放电，和2.如果恢复放电成功阻止锥体神经元 过度兴奋和相关的脊柱丧失。在目标1中，我预测斑块前AD的FS-PV放电改变是 由VGC的生物物理变化引起。为了评估这些潜在的变化，我将使用电生理学 测量VGC生物物理变化的方法。我还将从野生型和AD中分离活的FS-PV中间神经元， 小鼠模型以评估VGC mRNA表达变化。在目标2中，我预测FS-PV的恢复放电 斑块前AD中的中间神经元将防止锥体神经元过度兴奋性和相关的棘丢失。在这 目的，恢复FS-PV中间神经元的放电将使用两种方法实现：化学遗传学和细胞- 类型特异性基因治疗。将评估锥体神经元过度兴奋和形态学（棘丢失） 使用膜片钳电生理学和双光子成像。这项提案的结果将提供一个早期的 AD干预的点和具有神经变性预防潜力的可转化治疗方法。

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.