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底物，也可以是对神经元损伤反应的介体（反应性可塑性）。反应性可塑性，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。但是，塑性机制的过度刺激会导致异常发芽，从而增加了可塑性负担并导致次级神经变性。异常发芽是阿尔茨海默氏病的早期特征，可检测到的缠结形成和广泛的神经元丧失。因此，在疾病的早期阶段阻止异常发芽可能有助于减轻可塑性负担并防止神经变性。在初步研究中，我们建立了一个异常发芽的体外AD模型。使用此模型，我们发现Abeta通过局灶性粘附信号级联反对Rac1和Cdc42的活性引起异常发芽。我们进一步证明，RAC/CDC42的激活和局灶性粘附信号对于这种ABETA诱导的反应性可塑性至关重要。 RAC/CDC42的激活取决于它们通过甲酸酯合成途径中的类异丙磷酸盐（GGPP）（GGPP）的原始化。已经证明异普尼因可以调节RAC/CDC42的活性和局灶性粘附的结构。因此，调节类异戊二烯水平可以减少ABETA介导的RAC/CDC42活性和局灶性粘附信号的失调。此外，流行病学研究表明，他汀类药物是一组抑制类异丙裔合成的药物，降低了阿尔茨海默氏病的患病率。我们假设大脑中的类异丙基水平决定了包括Abeta在内的环境兴奋剂的反应性可塑性响应。因此，阿尔茨海默氏病的可塑性负担减轻。可以彻底实现大脑中类异型水平的操纵。为了调查我们是否可以通过调节类异丙素水平来减少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是否修改了a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，我们将能够对类吸引力在调节神经元可塑性中的作用以及他汀类药物在减轻阿尔茨海默氏病的可塑性负担方面的作用。