Isoprenoids and aberrant sprouting in 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（反应性可塑性）反应的介体。反应性可塑性，包括轴突和树突发芽和反应性突触形成，可能有助于神经元损伤后神经功能的恢复。然而，过度刺激可塑性机制会导致异常发芽，从而增加可塑性负担，导致继发性神经退行性变。异常发芽是阿尔茨海默病的早期特征。进行可检测的缠结形成和广泛的神经元损失。因此，在疾病的早期阶段阻断异常发芽可能有助于减少可塑性负担并防止神经退行性变。在初步研究中，我们建立了一个异常发芽的体外AD模型。使用该模型，我们发现Abeta通过黏着斑信号级联刺激Rac 1和Cdc 42的活性来诱导异常发芽。我们进一步证明了Rac/Cdc 42和粘着斑信号的激活对于这种Abeta诱导的反应性可塑性是必不可少的。Rac/Cdc 42的活化依赖于它们被香叶基香叶基焦磷酸（GGPP）（在甲羟戊酸合成途径中合成的类异戊二烯）的异戊烯化。类异戊二烯已被证明可以调节Rac/Cdc 42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A β介导的Rac/Cdc 42活性和粘着斑信号传导的失调。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，降低阿尔茨海默病的患病率。我们推测，类异戊二烯水平在大脑中决定了反应性可塑性反应的环境刺激剂，包括β-淀粉样蛋白，从而减少可塑性负担在阿尔茨海默病。可以通过操纵大脑中的类异戊二烯水平来实现。为了研究我们是否可以通过调节类异戊二烯水平来减少A β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A β介导的信号传导的影响;（2）GGPP是否修饰A β诱导的异常发芽;（3）抑制类异戊二烯合成对A β诱导的信号传导和异常发芽的影响。通过完成拟议的研究，我们将能够提供显着的洞察类异戊二烯在调节神经元可塑性的作用和他汀类药物在减少阿尔茨海默病的大脑中的可塑性负担的可能机制。

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.