NGF SIGNALING IN MODELS OF AGE RELATED NEURODEGENERATION

年龄相关神经退行性变模型中的 NGF 信号传导

基本信息

批准号：
6533821
负责人：
William C Mobley
金额：
$ 32.62万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-09-15 至 2005-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6533821
关键词：
Alzheimer's disease Downs syndrome acetylcholine aging apolipoprotein E biological signal transduction confocal scanning microscopy gene targeting genetic models genetically modified animals growth factor receptors laboratory mouse neural degeneration neuropathology neurotrophic factors prosencephalon protein transport tissue /cell culture

项目摘要

The broad long-term goal is to elucidate the mechanisms responsible for the dysfunction and loss of neurons in degenerative neurological disorders. In Alzheimer's disease (AD) and Down syndrome (DS), age- related degeneration of basal forebrain cholinergic neurons (BFCNs) contributes significantly to dementia. Defining the molecular events leading to BFCN degeneration would significantly advance our understanding of pathogenesis. In studies on the Ts65Dn mouse, a genetic model for DS, we documented age-related degeneration of BFCNs. Nerve growth factor (NGF) is essential to the function of normal BFCNs and recent findings suggest that failed NGF signaling contributes to their degeneration of Ts65Dn. We will test the hypothesis: that a failure in NGF signaling is responsible for the degeneration (i.e. progressive dysfunction) of BFCNs in the Ts65Dn mouse. The proposed Specific Aims are: 1) To characterize the functional status of BFCNs and document age-related dysfunction of these neurons in Ts65Dn mice. Using unbiased stereology, biochemical and behavioral studies we will document the time of onset of BFCN dysfunction in Ts65Dn mice. 2) To determine if NGF signaling is defective in BFCNs in Ts65Dn and, if so, to determine whether the abnormality predate degeneration of BFCNs. Abnormal NGF retrograde transport will be used to document the existence of a signaling defect and biochemical studies will define its nature and time of onset. 3) To determine whether disrupting NGF signaling reproduces the cholinergic abnormalities seen in Ts65Dn. If the NGF signaling defect demonstrated in Aim 2 is sufficient to produce the degeneration of BFCNs in Ts65Dn, animals defective for NGF signaling should show the same degenerative events. We will examine mice treated with NGF antibodies to sequester endogenous NGF, mice in which one copy of the NGF gene has been disrupted, and mice in which both copies of the gene for the NGF TrkA receptor has been knocked-out. 4) To define NGF actions on degenerating BFCNs in Ts65Dn. Current data suggest that NGF may be capable of reversing other aspects of BFCN degeneration. In this Aim, we will determine whether NGF reverses the degenerative phenotypes defined in Aim 1. 5) To determine whether BFCN degeneration is found in other genetic models of Ds and AD and, if so, whether failed NGF signaling is present. We will examine BFCNs in several models of AD. If BFCN atrophy is detected, we will determine whether there is an abnormality of NGF signaling. We will also examine Ts65Dn animals expressing either human Apo E3 or E4 to determine whether, as expected, BFCN degeneration is worse in ApoE4 expressing mice. Evidence that abnormal NGF signaling is responsible for BFCN degeneration in models of AD and DS will give important new insights into pathogenesis and may suggest novel approaches to prevent or reverse dementia in these patients.

广泛的长期目标是阐明负责的机制退化神经系统中神经元的功能障碍和丧失疾病。在阿尔茨海默氏病（AD）和唐氏综合症（DS）中，年龄 - 基础前脑胆碱能神经元（BFCN）的相关变性对痴呆症有重大贡献。定义分子事件导致BFCN变性将大大推动我们的对发病机理的理解。在TS65DN小鼠的研究中 DS的遗传模型，我们记录了BFCN与年龄相关的变性。神经生长因子（NGF）对于正常BFCN的功能至关重要最近的发现表明，失败的NGF信号导致他们的TS65DN退化。我们将检验以下假设： NGF信号失败是导致变性的（即 TS65DN小鼠中BFCN的进行性功能障碍。提议具体目的是：1）表征BFCN的功能状态和这些神经元在TS65DN小鼠中与年龄相关的功能障碍。使用公正的立体学，生化和行为研究我们将记录 TS65DN小鼠中BFCN功能障碍的发作时间。 2）确定如果NGF信号在TS65DN中的BFCN中有缺陷，则为确定异常是否早于BFCN的变性。 NGF异常逆行运输将用于记录存在信号缺陷和生化研究将定义其性质和发作时间。 3）确定是否破坏NGF信号传导再现TS65DN中看到的胆碱能异常。如果是NGF AIM 2中证明的信号传导缺陷足以产生 TS65DN中BFCN的变性，动物在NGF信号中有缺陷应该显示相同的退行性事件。我们将检查接受治疗的小鼠使用NGF抗体隔离内源性NGF，其中一个拷贝 NGF基因已被破坏，并且两种副本的小鼠 NGF TRKA受体的基因已被淘汰。 4）定义NGF 在TS65DN中对BFCN进行退化的作用。当前数据表明NGF 可能能够逆转BFCN变性的其他方面。在这个目的，我们将确定NGF是否逆转退化表型在目标1。5）中定义为确定是否发现BFCN变性在其他DS和AD的遗传模型中，如果是的，则NGF是否失败存在信号。我们将在几种AD模型中检查BFCN。如果检测到BFCN萎缩，我们将确定是否存在 NGF信号传导异常。我们还将检查TS65DN动物表达人apo e3或e4以确定是否按预期 APOE4表达小鼠的BFCN变性较差。证据异常NGF信号导致模型中的BFCN变性 AD和DS将为发病机理提供重要的新见解，可能提出了预防或反向痴呆的新方法患者。