Isoprenoids and aberrant sprouting in Alzheimer's disease

类异戊二烯和阿尔茨海默病中的异常发芽

• 批准号: 7130602
• 负责人: YAN ZHOU
• 金额: $ 6.42万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7130602
• 关键词: Alzheimer' s disease; antihypercholesterolemic agent; biological signal transduction; biosynthesis; inhibitor /antagonist; isoprenoid; neural degeneration; neural plasticity; neuronal guidance; neuropharmacology; prenylation

DESCRIPTION (provided by applicant): Neuroplasticity can be either a substrate of learning and memory or a mediator of responses to neuronal injury (reactive plasticity). Reactive plasticity, including axonal and dendritic sprouting and reactive synaptogenesis, may help the recovery of neuronal function after neuronal injury. However, overstimulation of plasticity mechanism causes aberrant sprouting, which increases plasticity burden and leads to secondary neurodegeneration. Aberrant sprouting is an early feature of Alzheimer's disease., proceeding detectable tangle formation and extensive neuron loss. Therefore, blocking aberrant sprouting in the early stage of the disease may help to reduce plasticity burden and prevent neurodegeneration. In preliminary studies, we established an in vitro AD model of aberrant sprouting. Using this model, we found that Abeta induced aberrant sprouting through the stimulation of the activity of Rac1 and Cdc42 via focal adhesion signaling cascade. We further demonstrated that both activation of Rac/Cdc42 and focal adhesion signaling are essential for this Abeta-induced reactive plasticity. The activation of Rac/Cdc42 depends on their prenylation by geranylgeranyl pyrophosphate (GGPP), an isoprenoid synthesized in the mevalonate synthetic pathway. Isoprenoids have been shown to regulate both the activities of Rac/Cdc42 and the structure of focal adhesion. Thus, modulating isoprenoid levels could reduce Abeta-mediated dysregulation of Rac/Cdc42 activity and focal adhesion signaling. In addition, epidemiological studies show that statins, a group of drugs that inhibit isoprenoid synthesis, reduce the prevalence of Alzheimer's disease. We hypothesize that isoprenoid level in the brain determines reactive plasticity response to environmental stimulants including Abeta; thus, decrease of plasticity burden in Alzheimer's disease. can be achieved thorough the manipulation of isoprenoid levels in the brain. To investigate whether we can reduce Abeta-induced plasticity burden through regulating isoprenoid levels, we will use established model system and methods to investigate: (1) the effect of GGPP on Abeta-mediated signaling; (2) whether GGPP modifies Abeta- induced aberrant sprouting; (3) the effect of inhibiting isoprenoid synthesis on Abeta-induced signaling and aberrant sprouting. By completion of the proposed studies, we will be able to provide significant insight into the role of isoprenoids in the regulation of neuronal plasticity and a possible mechanism of statins in reducing the plasticity burden in the brains of Alzheimer's disease.

描述（由申请人提供）：神经可塑性可以是学习和记忆的基础，也可以是对神经元损伤反应的介质（反应性可塑性）。反应可塑性，包括轴突和树突发芽以及反应性突触发生，可能有助于神经元损伤后神经元功能的恢复。然而，过度刺激可塑性机制会导致异常萌芽，从而增加可塑性负担并导致继发性神经变性。异常发芽是阿尔茨海默氏病的早期特征，会导致可检测到的缠结形成和广泛的神经元损失。因此，在疾病早期阻止异常发芽可能有助于减轻可塑性负担并预防神经退行性变。在初步研究中，我们建立了异常发芽的体外 AD 模型。使用该模型，我们发现 Abeta 通过粘着斑信号级联刺激 Rac1 和 Cdc42 的活性来诱导异常发芽。我们进一步证明 Rac/Cdc42 的激活和粘着斑信号传导对于 Abeta 诱导的反应可塑性至关重要。 Rac/Cdc42 的激活取决于其被香叶基香叶基焦磷酸 (GGPP) 的异戊二烯化，GGPP 是甲羟戊酸合成途径中合成的类异戊二烯。类异戊二烯已被证明可以调节 Rac/Cdc42 的活性和粘着斑的结构。因此，调节类异戊二烯水平可以减少 Abeta 介导的 Rac/Cdc42 活性和粘着斑信号传导失调。此外，流行病学研究表明，他汀类药物（一组抑制类异戊二烯合成的药物）可以降低阿尔茨海默病的患病率。我们假设大脑中的类异戊二烯水平决定了对包括 Abeta 在内的环境刺激物的反应可塑性反应；因此，减少阿尔茨海默病的可塑性负担。可以通过控制大脑中的类异戊二烯水平来实现。为了研究是否可以通过调节类异戊二烯水平来减少Abeta诱导的可塑性负担，我们将使用已建立的模型系统和方法来研究：（1）GGPP对Abeta介导的信号传导的影响； (2) GGPP是否改变Abeta诱导的异常发芽； (3)抑制类异戊二烯合成对Abeta诱导的信号传导和异常发芽的影响。通过完成拟议的研究，我们将能够深入了解类异戊二烯在神经元可塑性调节中的作用，以及他汀类药物减少阿尔茨海默病大脑可塑性负担的可能机制。