NEURAL REGULATION AND PHYSIOLOGIC ACTIONS OF THE APP FAMILY OF PROTEINS

与阿尔茨海默病相关的基因突变的性质强烈表明 淀粉样蛋白表达或加工的异常 前体蛋白(APP)导致AD的病理改变。衰老本身怎么可能， 这是绝大多数AD病例的基础，导致类似的 病理学？最新的体外证据表明，分泌的片段 APP，APP，改善神经元CA动态平衡，促进神经元 存活；分泌的ABETA具有相反的效果。对这一点的破坏 神经毒性ABeta和神经保护应用程序之间的平衡，现在 这似乎是一种令人信服的机制，可能有助于AD的病理。 同源蛋白，淀粉样前体蛋白(APLP)可能 在APP生物学中也有功能和病理生理作用。vbl.使用 电生理记录技术、荧光钙指示剂染料 和神经毒性测试，我们设计了实验来检验 APP、APLP和APLP调节CASE涉及的重要过程 动态平衡包括：电压依赖性钙通道，强健 突触活动、谷氨酸受体激活和钙释放 内部商店。由于应用程序、ABeta和APLP是保密的，因此存在于 突触终末，调制神经元内[Ca]，并 在兴奋性毒性模型中的神经保护作用，我们怀疑它们在 在突触传递中发挥重要作用。为了测试这一点，我们计划 在展示的模型系统中检查应用程序和APLP的影响 容易控制的突触活动。 已知的APP在非神经组织中的调节机制 新发现的功能性质，强烈表明合成 APP家族蛋白的分泌受固有的 神经过程。在这项提案中，我们计划仔细研究 神经递质-受体激活、热和代谢的影响 神经应激，并激活APP、APP、ABETA上的第二信使系统 APLP的合成和分泌。我们的初步数据显示， 各种生理上重要的条件会对 APP、APP和APLP在神经元和神经胶质细胞及其覆盖的介质中的水平。 与衰老相关的疾病，如基因突变，可能会改变 这些分子的功能活性、加工或合成 导致阿尔茨海默病的神经退化。研究衰老带来的影响 本身，我们将比较该应用程序的监管和功能属性 成熟的、一个月前的培养物中的蛋白质家族 超过6个月。我们的目标是发现 APP系列的各个成员的属性和监管 在正常和应激的中枢神经系统组织中，分子是相互协调的。我们的中央 假说是，这种关系的失调可能会对 神经细胞钙稳态，从而促进神经退行性变 广告。

The nature of the genetic mutations associated with AD strongly suggest that an abnormality in the expression or processing of the amyloid precursor protein (APP) leads to AD pathology. How might aging itself, which underlies the vast majority of AD cases, lead to a similar pathology? Recent in vitro evidence establishes that secreted fragments of APP, APPS, improve neuronal CA ++ homeostasis and promote neuronal survival; secreted ABeta has opposite effects. A disruption of this balance, between the neurotoxic ABeta and the neuroprotective APPS, now seems a compelling mechanism which might contribute to AD pathology. Homologous proteins, the amyloid precursor-like proteins (APLPs), likely have functional and pathophysiologic roles in APP biology as well. Using electrophysiologic recording techniques, fluorescent Ca++ -indicator dyes and neurotoxicity assays, we have designed experiments to examine how APPs and APLPs and APLPs modulate important processes involved in Ca++ homeostasis including: voltage-dependent calcium channels, robust synaptic activity, glutamate-receptor activation and Ca++ release from internal stores. Since APPs, ABeta, and APLPs are secreted, present in synaptic terminals, modulate intraneuronal [Ca++], and are neuroprotective in excitotoxicity models, we suspect they play an important role in synaptic transmission. To test this, we plan to examine the effects of APPs and APLPs in a model system that exhibits easily controlled synaptic activity. Known mechanisms of APP regulation in non-neural tissues combined with newly found functional properties, strongly suggest that the synthesis and secretion of the APP family of proteins are regulated by inherently neural processes. In this proposal we plan to carefully examine the effects of neurotransmitter-receptor activation, thermal and metabolic neural stress, and activated second messenger systems on APP, APPs, ABeta and APLP synthesis and secretion. Our preliminary data indicate that a variety of physiologically important conditions differentially affect APP, APPs and APLP levels in neurons and glia and their overlying media. Aging-related disorders, like genetic mutations, could alter the functional activity, processing or synthesis of these molecules contributing to AD neurodegeneration. To study effects due to aging itself, we will compare regulatory and functional properties of the APP family of proteins in mature, month old cultures with cultures grown for greater than 6 months. Our goal is to discover how the functional properties and regulation of the various members of the APP family of molecules are coordinated in normal and stressed CNS tissue. Our central hypothesis is that a disorder in this relationship could adversely affect neuronal Ca++ homeostasis and thereby contribute to neurodegeneration in AD.