Role of APP and its Metabolites in Synaptic Degeneration

APP 及其代谢物在突触变性中的作用

• 批准号: 7038881
• 负责人: Lennart Mucke
• 金额: $ 49.42万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7038881
• 关键词: Alzheimer' s disease; amyloid proteins; behavior test; cognition disorders; confocal scanning microscopy; electrophysiology; enzyme linked immunosorbent assay; genetically modified animals; hippocampus; laboratory mouse; light microscopy; nerve /myelin protein; neural degeneration; neural transmission; platelet derived growth factor; protein structure function; protein tyrosine kinase; statistics /biometry; synapses; synaptophysin; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): Alzheimer's disease (AD), the main cause of age-related dementia, is increasing in prevalence due to the increasing number of elderly in our population. AD is associated with prominent impairments of neurons and synapses and with an abnormal accumulation of amyloid-B peptides (AB) in the brain. AB, which is derived from the amyloid precursor protein (APP), appears to play a causal role in AD, although it remains uncertain how it erodes cognitive functions and how this process can be prevented or reversed. The results we obtained during the preceding funding period have begun to shed light on these questions. We determined that human APP (hAPP) transgenic mice producing high levels of human Af5 in the brain have an AD-like pattern of synaptic alterations (previous Aim 1), that the enzyme Fyn is involved in some AB-dependent synaptic alterations (previous Aim 2), that premature mortality and neuronal deficits in hAPP mice can be prevented or delayed by the genetic modulation of Fyn or apolipoprotein E (previous Aim 3), and that the extent of cognitive deficits in hAPP mice is tightly linked to the neuronal depletion of factors that are regulated by excitatory synaptic activity (previous Aim 4). Some of these factors were also depleted in corresponding neuronal populations of humans with AD. These results provide a solid foundation for the current application and underline that we are in a good position to advance this interesting area of research. Here we propose to determine how exactly hAPP/Abeta interacts with Fyn-related signaling cascades to cause neuronal impairments (new Aim 1), whether the pharmacogenetic inhibition of Fyn can prevent and reverse neuronal deficits in hAPP mice (new Aim 2), whether hAPP/Abeta-dependent neuronal alterations are caused by an imbalance of excitatory and inhibitory synaptic activities (new Aim 3), and whether the pharmacological or genetic manipulation of neurotransmitter receptors or Fyn-related signaling pathways can prevent and reverse behavioral deficits in hAPP mice (new Aim 4). This study could reveal how increased levels of AB impair important cognitive functions such as learning and memory. It could also resolve whether these impairments can be prevented or reversed by therapeutic manipulation of synaptic activity and neuronal signaling. Ultimately, our study may provide useful guidance in the development of drugs to maintain and improve memory and other cognitive functions in AD.

描述（由申请人提供）：阿尔茨海默病（AD）是年龄相关性痴呆的主要原因，由于我国人口中老年人数量的增加，其患病率正在增加。AD与神经元和突触的显著损伤以及脑中淀粉样蛋白-B肽（AB）的异常积累相关。来自淀粉样前体蛋白（APP）的AB似乎在AD中起着因果作用，尽管它仍然不确定它如何侵蚀认知功能以及如何预防或逆转这一过程。我们在上一个供资期间获得的结果已开始阐明这些问题。我们确定，在脑中产生高水平人Af 5的人APP（hAPP）转基因小鼠具有AD样的突触改变模式。（先前的目的1），酶Fyn参与一些AB依赖性突触改变（先前的目的2），hAPP小鼠中的过早死亡和神经元缺陷可以通过Fyn或载脂蛋白E的遗传调节来预防或延迟。（先前的目的3），并且hAPP小鼠中认知缺陷的程度与由兴奋性突触活动调节的因子的神经元消耗紧密相关（先前的目的4）。这些因子中的一些在患有AD的人的相应神经元群体中也被耗尽。这些结果为当前的应用提供了坚实的基础，并强调我们处于有利地位，可以推进这一有趣的研究领域。在这里，我们建议确定hAPP/Abeta如何与Fyn相关的信号级联相互作用，从而导致神经元损伤（新目标1），Fyn的药物遗传学抑制是否可以预防和逆转hAPP小鼠中的神经元缺陷（新目标2），hAPP/A β依赖性神经元改变是否由兴奋性和抑制性突触活动的不平衡引起（新目标3），以及神经递质受体或Fyn相关信号通路的药理学或遗传学操作是否可以预防和逆转hAPP小鼠的行为缺陷（新目标4）。这项研究可以揭示AB水平的增加如何损害重要的认知功能，如学习和记忆。它还可以解决这些损伤是否可以通过突触活动和神经元信号的治疗操作来预防或逆转。最终，我们的研究可能为开发药物以维持和改善AD患者的记忆和其他认知功能提供有用的指导。