Isoprenoids and aberrant sprouting in Alzheimer's disease

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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.