Targeting FAAH to treat Alzheimers disease

描述（由申请人提供）：内源性大麻素系统是一种神经调节系统，影响广泛的生理过程，包括记忆和炎症。有证据表明，外源性和内源性大麻素具有神经保护作用，因此对大麻素治疗阿尔茨海默病的潜力感兴趣。体外研究表明，大麻素受体激活可以抑制或减少β-淀粉样蛋白斑块的沉积，并减少炎症，这是阿尔茨海默病的关键特征。此外，大麻素系统的激活具有神经保护作用。虽然这些发现表明大麻素可能有利于减轻与阿尔茨海默病相关的神经病理学，但很少有研究评估内源性大麻素系统的刺激是否可以减轻阿尔茨海默病体内模型中的认知缺陷和神经病理学。这些研究的目标将是检查是否通过抑制其主要降解酶脂肪酸酰胺水解酶（FAAH）来提高内源性大麻素anandamide的内源性水平，将对3xTg小鼠（阿尔茨海默病的体内模型）中的记忆障碍和神经病理学标志物具有有益作用。更具体地说，我们将确定重复施用FAAH抑制剂PF-3845是否改善学习和记忆，并预防或延迟阿尔茨海默病的神经病理过程。从这些原则研究的证据的发现可能会导致识别一种新的治疗剂的记忆缺陷和神经病理学与阿尔茨海默氏病。

DESCRIPTION (provided by applicant): The endogenous cannabinoid system is a neuromodulatory system that affects a wide range of physiological processes, including memory and inflammation. Evidence indicates that exogenous and endogenous cannabinoids are neuroprotective and thus there is interest in the therapeutic potential of cannabinoids in Alzheimer's disease. In vitro studies have shown that cannabinoid receptor activation can inhibit or reduce the deposition of beta-amyloid plagues and decrease inflammation, critical features of Alzheimer's disease. Moreover activation of the cannabinoid system has neuroprotective effects. While these findings indicate that cannabinoids may be beneficial in attenuating the neuropathology associated with Alzheimer's disease, very few studies have evaluated if stimulation of the endocannabinoid system can attenuate cognitive deficits and neuropatholgy in in vivo models of Alzheimer's disease. The goal of these studies will be to examine whether elevating endogenous levels of the endocannabinoid anandamide via inhibition of its primary degradative enzyme fatty acid amide hydrolase (FAAH), will have beneficial effects on memory impairments and neuropathological markers in 3xTg mice, an in vivo model of Alzheimer's disease. More specifically, we will determine whether repeated administration of the FAAH inhibitor PF-3845 improves learning and memory and prevents or delays neuropathological processes of Alzheimer's disease. The findings from these proofs of principle studies may lead to the identification of a new therapeutic agent for memory deficits and neuropathology associated with Alzheimer's disease.