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

项目总结 阿尔茨海默病(AD)是痴呆症最常见的形式，导致神经元突触(脊椎)丢失，大脑 萎缩，以及最终的记忆丧失。尽管AD预计将从580万受影响的美国人增加到138万人 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 病理性淀粉样β斑块和tau缠结。然而，最近的研究表明，斑块和斑块纠缠 病理学在疾病中出现的时间相对较晚。最近对AD患者和疾病模型的研究将 过度兴奋，锥体神经元放电增加，在淀粉样β斑块病理之前，提供了早期 疾病干预点。锥体神经元过度兴奋是一种现象，可由 抑制性/兴奋性输入失衡。最近的文献表明，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，特别是快速尖峰小白蛋白(FS- Pv)中间神经元。FS-PV中间神经元在斑块前驱相显示动作电位放电改变 阿尔茨海默病小鼠模型的病理改变，导致锥体神经元过度兴奋。已知的发射模式是 FS-PV中间神经元可以通过改变特定基因的表达或生物物理性质而改变 电压门控通道(VGC)。这项建议旨在确定1.变更的机械基础 FS-PV中间神经元放电；2.如果恢复放电能成功阻止锥体神经元 过度兴奋和相关的脊椎丧失。在目标1中，我预测斑块前AD患者的FS-PV放电改变是 由VGC中的生物物理变化引起。为了评估这些电位变化，我将使用电生理学 方法测量VGC的生物物理变化。我还将从野生型和AD中分离出活的FS-PV中间神经元 用小鼠模型评估VGC基因表达的变化。在目标2中，我预测FS-PV的恢复发射 斑块前AD中的中间神经元将防止锥体神经元过度兴奋和相关的脊椎丢失。在这 目的：通过两种方法实现FS-PV中间神经元的恢复放电：化学遗传学和细胞遗传学。 特定类型的基因治疗。将评估锥体神经元的超兴奋性和形态(脊椎丢失) 采用膜片钳电生理学和双光子成像技术。这项提议的结果将提供一个早期的 阿尔茨海默病的干预要点和一种具有预防神经退行性变潜力的可翻译治疗方法。

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.