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.

我们将研究淀粉样蛋白前体蛋白（APP）和APP衍生的淀粉样β肽（ABETA）在阿尔茨海默氏病（AD）的发病机理中，这是衰老中枢神经系统中最常见的蛋白质病。我们以前在转基因小鼠的神经元中过表达了野生型人类应用程序（HAPP [wt]）或家族性的人类应用程序（HAPP [FAD]）。这些小鼠中的淀粉样蛋白沉积取决于42-氨基酸的绝对水平和相对水平 Abeta的形式（Abeta1-42）以及这种原纤维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中无关，表明ABETA的神经毒性与斑块无关。载脂蛋白（APO）E3的表达，而不是APOE4的表达，阻止了或延迟的突触损失和HAPP [FAD]/APOE双重转基因小鼠中的突触损失和记忆障碍。老化的HAPP [FAD]小鼠，Abeta1-42水平高在基底前脑中还损失了胆碱能神经元。最近，我们发现HAPP [FAD]小鼠中的行为缺陷与齿状回的钙结合蛋白Calbindin-D28 K（CB）的降低密切相关。在AIM 1中，我们将确定为什么在HAPP [FAD]小鼠中齿状回的神经元CB水平强烈降低，而仅在HAPP [WT]小鼠中最少。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AIM 2中，我们将检查CB减少是否在Abeta诱导的行为缺陷的发展中起关键作用。我们将将CB水平与HAPP小鼠的功能神经元缺陷相关联，并检查CB的可调节过表达是否会调节这些缺陷。在AIM 3中，我们将表征HAPP小鼠中的胆碱能缺陷，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础前脑系统，评估它们在脑源性神经营养的表达，运输还是释放中是否存在缺陷因素，并测试增加乙酰胆碱水平是否会改善其行为缺陷。在AIM 4中，我们将检查该程序的其他组成部分中生成的双重转基因小鼠，以确定APOE和Alpha--核素是否调节APOE诱导的神经元缺陷的发展以及如何调节。这些研究将阐明从Abeta的致病组装到功能性神经系统下降的分子级联反应。提出的实验跟进了固体的初步数据，并积极地有助于该程序的凝聚力。他们的成功取决于所提出的计划的大多数（如果不是全部）组成部分。