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: 7294265
• 负责人: YAN ZHOU
• 金额: $ 6.47万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 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 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7294265
• 关键词: Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Area; Biological Models; Brain; Defect; Depth; Disease; Epidemiologic Studies; Focal Adhesions; Foundations; Future; Hippocampal Formation; In Vitro; Learning; Mediating; Mediator of activation protein; Memory; Methods; Modeling; Molecular; Neocortex; Nerve Degeneration; Neurobiology; Neuronal Injury; Neuronal Plasticity; Neurons; Pathology; Pathway interactions; Pharmaceutical Preparations; Presynaptic Terminals; Prevalence; Recovery; Regulation; Research; Role; Secondary to; Senile Plaques; Signal Transduction; Staging; Structure; Synapses; axonal sprouting; base; geranylgeranyl pyrophosphate; in vivo; insight; isoprenoid; mevalonate; neurofibrillary tangle formation; neuron loss; novel; prenylation; prevent; response; synaptogenesis

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(申请人提供)：神经可塑性可以是学习和记忆的底物，也可以是神经元损伤反应的中介(反应性可塑性)。反应性可塑性，包括轴突和树突的萌发以及反应性突触的形成，可能有助于神经元损伤后神经功能的恢复。然而，对可塑性机制的过度刺激会导致异常发芽，从而增加可塑性负担，导致继发性神经变性。异常发芽是阿尔茨海默病的早期特征，可检测到的缠结形成和广泛的神经元丢失。因此，在疾病的早期阶段阻断异常发芽可能有助于减轻可塑性负担，防止神经退变。在初步研究中，我们建立了一种异常萌发的体外AD模型。利用这一模型，我们发现Abeta通过局部黏附信号级联刺激了rac1和CDc42的活性，从而诱导了异常萌发。我们进一步证明，RAC/CDC42的激活和粘着斑信号在Abeta诱导的反应可塑性中都是必不可少的。RAC/Cdc42的活化依赖于它们被香叶基香叶基焦磷酸(GGPP)的预烯基化，GGPP是甲氧戊酸合成途径中合成的一种异戊二烯类化合物。异戊二烯类化合物既能调节RAC/Cdc42的活性，又能调节焦点黏附的结构。因此，调节异戊二烯水平可以减少Abeta介导的RAC/CDC42活性和粘着斑信号的失调。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性可塑性反应，从而降低了阿尔茨海默病的可塑性负担。可以通过操纵大脑中类异戊二烯的水平来实现。为了研究是否可以通过调节类异戊二烯水平来减轻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介导的信号转导的影响；(2)GGPP是否改变Abeta诱导的异常发芽；(3)抑制异戊二烯合成对Abeta诱导的信号和异常发芽的影响。通过拟议的研究，我们将能够对异戊二烯类化合物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病大脑可塑性负担方面的可能机制提供重要的见解。