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

• 批准号: 6169599
• 负责人: William C Mobley
• 金额: $ 31.18万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-15 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6169599
• 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

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 退行性神经系统中神经元的功能障碍和损失 失调。 在阿尔茨海默病 (AD) 和唐氏综合症 (DS) 中，年龄 基底前脑胆碱能神经元（BFCN）的相关变性 显着促进痴呆症。 定义分子事件 导致 BFCN 退化将显着促进我们的 了解发病机制。 在 Ts65Dn 小鼠的研究中， DS 的遗传模型中，我们记录了 BFCN 与年龄相关的退化。 神经生长因子 (NGF) 对于正常 BFCN 的功能至关重要 最近的研究结果表明，失败的 NGF 信号传导会导致 他们的 Ts65Dn 变性。 我们将检验这个假设： NGF 信号传导的失败是导致退化的原因（即 Ts65Dn 小鼠中 BFCN 的进行性功能障碍。 拟议的 具体目标是： 1) 描述 BFCN 的功能状态和 记录了 Ts65Dn 小鼠中这些神经元与年龄相关的功能障碍。 使用 我们将记录公正的体视学、生化和行为研究 Ts65Dn 小鼠中 BFCN 功能障碍的发生时间。 2）确定 如果 Ts65Dn 中的 BFCN 中的 NGF 信号有缺陷，并且如果是这样，则 确定异常是否早于 BFCN 的退化。 异常的NGF逆行运输将被用来记录其存在 信号缺陷和生化研究将确定其性质和 发病时间。 3) 确定是否破坏NGF信号传导 再现了 Ts65Dn 中看到的胆碱能异常。 如果神经生长因子 目标 2 中证明的信号缺陷足以产生 Ts65Dn 中 BFCN 的退化，NGF 信号传导缺陷的动物 应表现出相同的退化事件。 我们将检查接受治疗的小鼠 具有隔离内源性 NGF 的 NGF 抗体的小鼠，其中一个拷贝 NGF 基因的两个拷贝都被破坏了 NGF TrkA 受体基因已被敲除。 4) 定义NGF 对 Ts65Dn 中退化 BFCN 的作用。 目前的数据表明 NGF 可能能够逆转 BFCN 退化的其他方面。 在这个 目的，我们将确定NGF是否逆转退行性表型 目标 1 中定义。 5) 确定是否发现 BFCN 退化 在 Ds 和 AD 的其他遗传模型中，如果是，NGF 是否失败 信令存在。 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信号异常。我们还将检查 Ts65Dn 动物 表达人 Apo E3 或 E4 以确定是否如预期那样， BFCN 变性在 ApoE4 表达小鼠中更为严重。 有证据表明 异常的 NGF 信号传导导致模型中 BFCN 退化 AD 和 DS 的研究将为发病机制提供重要的新见解，并可能 建议预防或逆转这些人群痴呆症的新方法 患者。