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.

项目概要 阿尔茨海默病 (AD) 的初始阶段似乎与电活动和突触升高相关 大脑区域的异常首先受到病理学的影响，这种病理学上转向兴奋。 表明这些区域内的突触兴奋和抑制平衡（E/I 比）发生了变化 （例如，内嗅皮质），这反过来可能会加速活动依赖性 AD 病理学，但是，目前还没有这种机制。 人脑 E/I 比率的定量、区域测量，以及 AD 中该测量值的变化 在导致该提议的初步工作中，我们发现了抑制信号传导的证据。 AD 早期阶段的 Gephyrin 表达水平的紊乱，Gephyrin 是一种抑制性突触后突触密度。 (iPSD) 蛋白质，在供体死后大脑的内嗅皮层神经元细胞体中减少 此外，通过微移植诊断出患有轻度认知障碍（MCI），这是 AD 的前驱阶段。 我们发现，来自人类 AD 供体颞叶皮质的受体进入非洲爪蟾卵母细胞 GABA 受体 (GABAAR) 的电生理学异常表明抑制性音调降低 但重要的是，尚不清楚这些集体改变是否也发生在突触水平上。 考虑到这些初步发现，我们认为 1) MCI 是 AD 中出现的。 其特点是大脑区域的 E/I 比率异常大，尤其是 AD 早期受影响的区域；2) E/I 比率 不平衡是由突触兴奋性或抑制性受体聚集受损或改变引起的 主要突触谷氨酸和 GABA 受体（GluR 和 GABAAR）的电生理特性。 这一一般假设将在两个具体目标中进行评估，目标 1 将测试是否存在具体目标。 MCI 中兴奋性与抑制性突触后密度 (ePSD/iPSD) 蛋白比率的兴奋性改变 AD 与对照的研究将使用荧光解卷积断层扫描 (FDT)，该技术由部分机构开发。 我们的研究小组，因此 PSD 标记的免疫标记是在尺寸限制内测量的 3D 重建的突触；FDT 分析将确定是否基于计数的促兴奋 E/I 比率， 表征和区分 MCI 与对照和 AD 病例的突触标记物的体积和强度。 为了补充解剖学工作，目标 2 将测试突触的电生理变化是否 使用突触膜微移植，受体有助于 MCI 和 AD 中更大的 E/I 比 (MSM)，一种新技术，可以对死后的 GluR 和 GABAAR 进行电生理学研究 人类脑组织。了解 MCI 和/或中突触 E/I 比率异常的程度。 AD 以及哪些 PSD 受体或蛋白质受到影响，将极大地促进靶向药理学 旨在恢复 E/I 平衡的干预措施可能会给早期表现的患者带来实质性益处 通过延迟或阻止 AD 进展而出现认知能力下降的迹象，目前影响约 530 万人 美国人。