MECHANISMS OF AMYLOID BETA PEPTIDE-INDUCED NEURONAL DEFICITS

β 淀粉样肽诱导的神经元缺陷的机制

基本信息

批准号：
7431634
负责人：
Lennart Mucke
金额：
$ 32.09万
依托单位：
J. DAVID GLADSTONE INSTITUTES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2008-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7431634
关键词：
Abbreviations Acetylcholine Acetylcholinesterase Ache Adult Age Aging Alzheimer&apos s Disease Amino Acids Amyloid beta-Protein Amyloid beta-Protein Precursor Amyloid deposition Analysis of Variance Apolipoprotein E Axonal Transport Behavior Behavioral Behavioral Mechanisms Biochemical Brain Brain-Derived Neurotrophic Factor Calcium Calcium Channel Calcium-Binding Proteins Calmodulin Choline O-Acetyltransferase Cholinergic Agents Cholinergic Receptors Controlled Study Cultured Cells Data Dependence Deposition Development Excision Glial Fibrillary Acidic Protein Glyceraldehyde 3-Phosphate Green Fluorescent Proteins Hippocampus (Brain)Homeostasis Human Immunization Impaired cognition Impairment Injection of therapeutic agent Lead Length Ligands Light Memory impairment Messenger RNA Modeling Molecular Molecular Analysis Molecular Chaperones Molecular Conformation Mus N-Methyl-D-Aspartate Receptors NGFR Protein Neuraxis Neuro-Oncological Ventral Antigen 2 Neurologic Neuron-Specific Enolase Neurons Optics Oxidoreductase Pathogenesis Pathway interactions Peptides Phosphotransferases Platelet-Derived Growth Factor Play Polyacrylamide Gel Electrophoresis Population Presynaptic Terminals Prions Protein Overexpression Proteins RNase protection assay Relative (related person)Research Personnel Reverse Transcriptase Polymerase Chain Reaction Role Senile Plaques Signal Transduction Slice Sodium Dodecyl Sulfate-PAGE Solid Structure of molecular layer of cerebellar cortex Superoxide Dismutase Synapses System Testing Tetracycline Tetracyclines Toxic effect Tracer Transforming Growth Factors Transgenic Mice Transgenic Organisms Water abeta deposition age related alpha synuclein amyloid peptide apolipoprotein E-3 apolipoprotein E-4 basal forebrain basal forebrain cholinergic neurons calbindin cholinergic cholinergic neuron density dentate gyrus dimer familial Alzheimer disease follow-up genetic manipulation improved in vivo interest mutant neurotoxic neurotoxicity presenilin prevent programs promoter receptor research study success synuclein transcriptional coactivator p75

项目摘要

We will study the roles of the amyloid precursor protein (APP) and APP-derived amyloid beta peptides (Abeta) in the pathogenesis of Alzheimer's disease (AD), the most frequent proteopathy of the aging central nervous system. We previously overexpressed wildtype human APP (hAPP[WT]) or familial AD-mutant human APP (hAPP[FAD]) in neurons of transgenic mice. Amyloid deposition in these mice depended on absolute and relative levels of the 42-amino acid form of Abeta (Abeta1-42) and on interactions of this fibrillogenic peptide with other molecules. Synaptic deficits correlated with Abeta levels but not with the deposition of Abeta into amyloid plaques, suggesting a plaque-independent neurotoxicity of Abeta. Expression of apolipoprotein (apo) E3, but not of apoE4, prevented or delayed synaptic loss and memory impairments in hAPP[FAD]/apoE doubly transgenic mice. Aged hAPP[FAD] mice with high Abeta1-42 levels also had losses of cholinergic neurons in the basal forebrain. Recently, we found that behavioral deficits in hAPP[FAD] mice were tightly correlated with reductions in the calcium-binding protein, calbindin-D28 K (CB), in the dentate gyrus. In Aim 1, we will determine why neuronal CB levels in the dentate gyrus are strongly diminished in hAPP[FAD] mice but only minimally in hAPP[WT] mice. We will assess the dependence of CB reductions on the levels of deposited and nondeposited Abeta species and evaluate the role of calcium channels in the CB alterations. In Aim 2, we will examine whether CB reduction plays a critical role in the development of Abeta-induced behavioral deficits. We will correlate CB levels with functional neuronal deficits in hAPP mice and examine whether regulatable overexpression of CB modulates these deficits. In Aim 3, we will characterize the cholinergic deficits in hAPP mice and assess their mechanisms and behavioral consequences. We will study the cholinergic basal forebrain system of these mice, evaluate whether they have deficits in the expression, transport, or release of brain-derived neurotrophic factor, and test whether increasing acetylcholine levels improves their behavioral deficits. In Aim 4, we will examine doubly transgenic mice to be generated in other components of this program to determine if and how the development of Abeta-induced neuronal deficits is modulated by apoE and alpha-synuclein. These studies will shed light on the molecular cascades that lead from the pathogenic assembly of Abeta to functional neurological decline. The proposed experiments follow up on a solid body of preliminary data and actively contribute to the cohesiveness of the program. Their success depends on most, if not all, components of the proposed program.

我们将研究淀粉样前体蛋白 (APP) 和 APP 衍生的淀粉样β肽 (Abeta) 在阿尔茨海默病 (AD) 发病机制中的作用，阿尔茨海默病是衰老中枢神经系统最常见的蛋白质病。我们之前在转基因小鼠的神经元中过表达野生型人类 APP (hAPP[WT]) 或家族性 AD 突变型人类 APP (hAPP[FAD])。这些小鼠中淀粉样蛋白的沉积取决于 42 个氨基酸的绝对和相对水平 Abeta (Abeta1-42) 的形式以及该原纤维形成肽与其他分子的相互作用。突触缺陷与 Abeta 水平相关，但与 Abeta 沉积到淀粉样蛋白斑块中无关，这表明 Abeta 具有不依赖于斑块的神经毒性。载脂蛋白 (apo) E3 的表达（而非 apoE4）可预防或延迟 hAPP[FAD]/apoE 双转基因小鼠的突触丧失和记忆障碍。 Abeta1-42 水平较高的老年 hAPP[FAD] 小鼠基底前脑的胆碱能神经元也有损失。最近，我们发现 hAPP[FAD] 小鼠的行为缺陷与齿状回中钙结合蛋白 calbindin-D28 K (CB) 的减少密切相关。在目标 1 中，我们将确定为什么 hAPP[FAD] 小鼠中齿状回中的神经元 CB 水平大幅降低，但 hAPP[WT] 小鼠中的降低幅度很小。我们将评估 CB 减少对沉积和非沉积 Abeta 物种水平的依赖性，并评估钙通道在 CB 改变中的作用。在目标 2 中，我们将研究 CB 减少是否在 Abeta 诱导的行为缺陷的发展中发挥关键作用。我们将把 CB 水平与 hAPP 小鼠的功能性神经元缺陷联系起来，并检查 CB 的可调节过度表达是否会调节这些缺陷。在目标 3 中，我们将描述 hAPP 小鼠的胆碱能缺陷并评估其机制和行为后果。我们将研究这些小鼠的胆碱能基底前脑系统，评估它们是否在脑源性神经营养物质的表达、运输或释放方面存在缺陷。因素，并测试增加乙酰胆碱水平是否可以改善他们的行为缺陷。在目标 4 中，我们将检查在该程序的其他部分中生成的双转基因小鼠，以确定 Abeta 诱导的神经元缺陷的发展是否以及如何受到 apoE 和 α-突触核蛋白的调节。这些研究将揭示从 Abeta 致病性组装到功能性神经功能衰退的分子级联反应。拟议的实验是对大量初步数据的后续研究，并积极促进了程序的凝聚力。他们的成功取决于拟议计划的大部分（如果不是全部）组成部分。