Synaptic Imbalance in Mild Cognitive Impairment and Alzheimer's Disease

轻度认知障碍和阿尔茨海默病的突触失衡

• 批准号: 9166406
• 负责人: JULIE C LAUTERBORN
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9166406
• 关键词: Address; Affect; Alzheimer' s Disease; American; Animal Model; Area; Autopsy; Base Ratios; Benzodiazepines; Binding Sites; Brain; Brain region; Cognitive; Cohort Studies; Complement; Defect; Development; Diagnosis; Disease; Electrodes; Electrophysiology (science); Equilibrium; FDA approved; Family; Fluorescence; Future; GABA Receptor; Generations; Glutamate Receptor; Glutamates; Human; Impaired cognition; Impairment; Individual; Intervention; Knowledge; Link; Measurement; Measures; Membrane; Neurons; Oocytes; Pathology; Patients; Pharmaceutical Preparations; Pharmacology; Phase Transition; Process; Production; Property; Protein Isoforms; Proteins; Publishing; Research; Seizures; Signal Transduction; Staging; Symptoms; Synapses; Synaptic Membranes; Synaptic Receptors; Techniques; Temporal Lobe; Testing; Therapeutic Intervention; Tissues; Work; Xenopus oocyte; aging brain; base; biophysical properties; brain tissue; cognitive control; cohort; density; desensitization; entorhinal cortex; gephyrin; hyperphosphorylated tau; improved; mild cognitive impairment; neuronal cell body; neurotransmission; novel; novel therapeutic intervention; postsynaptic; prevent; receptor; receptor function; reconstruction; targeted treatment; therapeutic development; tomography; voltage clamp

PROJECT SUMMARY Initial stages of Alzheimer’s disease (AD) appear to be correlated with elevated electrical activity and synaptic abnormalities in brain regions first affected by pathology. This pathologically shifting towards excitation suggests that there are alterations in the synaptic excitation and inhibition balance (E/I ratio) within these areas (e.g., entorhinal cortex), which in turn may accelerate activity-dependent AD pathology. However, there are no quantitative, regional measurements of the E/I ratio in the human brain, and alterations in this measure in AD are unknown. In preliminary work leading to this proposal, we have found evidence of inhibitory signaling disturbances at early stages of AD. Levels of Gephyrin expression, an inhibitory postsynaptic synaptic density (iPSD) protein, are reduced in entorhinal cortex neuronal cell bodies of postmortem brain from donors diagnosed with mild cognitive impairment (MCI), a prodromal stage of AD. In addition, by microtransplanting receptors from temporal cortices of human AD donors into Xenopus oocytes, we discovered electrophysiological abnormalities of GABA receptors (GABAARs) suggesting that inhibitory tone is reduced in AD. Importantly though, it is not known whether these collective alterations also occur at the level of synapses in AD or if they are emergent in MCI. Given these preliminary findings, we hypothesize that 1) MCI is characterized by abnormally large E/I ratios in brain regions particularly affected early on in AD and 2) E/I ratio imbalance is driven by impairment in the clustering of synaptic excitatory or inhibitory receptors, or by alteration of the electrophysiological properties of major synaptic glutamate and GABA receptors (GluRs and GABAARs). This general hypothesis will be evaluated in two Specific Aims. Aim 1 will test whether there are specific pro- excitatory alterations in the ratio of excitatory to inhibitory postsynaptic density (ePSD/iPSD) proteins in MCI and AD versus controls. Studies will use Fluorescence Deconvolution Tomography (FDT), developed by part of our research group, whereby immunolabeling of PSD markers are measured within the size constraints of synapses from 3D reconstructions; FDT analysis will determine if pro-excitatory E/I ratios based on counts, volume, and intensity of synaptic markers characterize and differentiate MCI from control and AD cases. Complementing the anatomical work, Aim 2 will test whether electrophysiological alterations of synaptic receptors contribute to larger E/I ratio in MCI and AD using the Microtransplantation of Synaptic Membranes (MSM), a novel technique that allows for electrophysiological studies of GluRs and GABAARs from postmortem human brain tissue. Understanding the degree to which abnormal synaptic E/I ratios are present in MCI and/or AD, and which PSD receptors or proteins are affected, would greatly facilitate targeted pharmacological interventions aimed at restoring E/I balance and may provide substantial benefit to patients showing early signs of cognitive decline by delaying or stopping the progression to AD which currently affects ~5.3 million Americans.

项目摘要 阿尔茨海默氏病（AD）的初始阶段似乎与升高的电活动和突触相关 大脑区域的异常首先受病理影响。这种病理转变向兴奋 表明这些领域内突触兴奋和抑制平衡（E/I比）有所改变 （例如，内嗅皮层），这又可能加速了依赖活性的AD病理学。但是，没有 人脑中E/I比的定量，区域测量，AD测量的改变 是未知的。在导致该建议的初步工作中，我们找到了抑制性信号的证据 AD早期阶段的干扰。 Gephyrin表达的水平，抑制性突触后突触密度 （IPSD）蛋白质，在供体后大脑的内嗅皮层神经元细胞体中降低 被诊断出患有轻度认知障碍（MCI），这是AD的前驱阶段。另外，通过微移植 来自人类AD供体临时皮质的受体进入爪蟾卵母细胞，我们发现 GABA受体（GABAARS）的电生理异常，表明抑制性张力降低 广告。但是重要的是，尚不清楚这些集体改变是否也发生在突触水平上 在广告中，或者如果它们在MCI中出现。鉴于这些初步发现，我们假设1）MCI是 在大脑区域的绝对大E/I比，特别是在AD中受到特别影响和2）E/I比的特征 不平衡是由突触兴奋或抑制受体聚类的损害驱动的，或者是通过改变的 主要突触谷氨酸和GABA受体的电生理特性（胶和Gabaars）。 该总体假设将以两个具体的目的进行评估。 AIM 1将测试是否有特定的pro- MCI中兴奋性与突触后密度（EPSD/IPSD）蛋白的兴奋性改变的兴奋性改变 和广告与控件。研究将使用荧光反卷积断层扫描（FDT），一部分开发 我们的研究小组，该小组在尺寸约束中测量了PSD标记的免疫标记 来自3D重建的突触； FDT分析将根据计数确定促启用性E/I比率是否 合成标记的体积和强度表征并区分了MCI与对照和AD病例。 补充解剖学工作，AIM 2将测试突触的电生理改变 接收器使用突触膜的微转移来促进MCI和AD的更大的E/I比率 （MSM），一种新型技术，允许对后尸体的gl毛和Gabaar进行电生理研究 人脑组织。了解MCI中存在异常突触E/I比的程度 AD以及哪些PSD受体或蛋白质受到影响，将极大地促进针对性的药物 旨在恢复E/I平衡的干预措施，并可能为早期显示的患者提供可观的好处 通过延迟或停止对AD的进展来减少认知能力下降的迹象，目前影响约530万 美国人。