Endocannabinoids in Neurodegenerative Diseases

描述（由申请人提供）：阿尔茨海默病（AD）是老年人痴呆症的最常见原因。阿尔茨海默病的特点是淀粉样斑块和神经原纤维缠结的积累和沉积、神经炎症、突触功能障碍、认知功能的进行性恶化和记忆丧失，并伴有广泛的神经元变性和神经元死亡。目前，还没有有效的药物来预防和治疗阿尔茨海默病，并阻止疾病的发展。这主要是由于我们对阿尔茨海默病的发展和神经病理机制的理解有限。内源性大麻素是天然存在的脂肪酸，具有抗炎和神经保护作用。最近，我们证明了外源性和内源性2-花生四烯醇甘油（2-AG）可以保护培养的海马神经元免受β -淀粉样蛋白诱导的神经变性和神经炎症。特别是，我们正在进行的研究表明，在AD动物模型中，通过抑制单酰基甘油脂肪酶（MAGL）（代谢2-AG的酶）来增强2-AG信号，可以显著降低a- β合成的关键酶- β位点APP切割酶1 （BACE1）的蛋白表达，减少a- β斑块的沉积、神经炎症和神经变性，并改善突触和认知功能。这意味着2-AG可能在对抗AD的发病机制和神经病理中起重要作用。先前的研究表明，在AD人和动物中，BACE1在蛋白水平而非mRNA水平的表达升高，这表明BACE1的表达在转录后水平受表观遗传机制的调控。我们的初步研究发现，针对BACE1的非编码microrna在AD人和动物的大脑中表达均显著下调，但在APP转基因AD动物中，当大脑2-AG水平升高时，其表达恢复到正常对照水平。因此，我们假设脑2-AG信号在预防和减少AD发病机制和神经病理中的作用是通过CB1受体依赖调节抑制BACE1的特异性mirna的表达，导致AD动物a - β的产生和积累减少，神经炎症和变性以及突触和认知功能的改善。该项目不仅将提供加强2-AG信号在预防或减少AD发病机制和神经病理学中的分子机制，而且将为开发和发现旨在预防和治疗AD或减缓AD进展的新型药物开辟新的领域。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common cause of dementia among older people. AD is characterized by accumulation and deposition of amyloid plaques and neurofibrillary tangles, neuroinflammation, synaptic dysfunction, progressive deterioration of cognitive function and loss of memory in association with widespread degenerated neurons and neuronal death. Currently, there are no effective medications to prevent and treat AD and halt the disease progression. This is largely due to our limited understanding of the mechanisms involved in the development and neuropathology of AD. Endocannabinoids are naturally occurring fatty acids displaying anti-inflammatory and neuroprotective properties. Recently we demonstrated that exogenous and endogenous 2-arachidonoylglycerol (2-AG) protects hippocampal neurons in culture against beta-amyloid- induced neurodegeneration and neuroinflammation. In particular, our ongoing research revealed that strengthening 2-AG signaling by inhibition of monoacylglycerol lipase (MAGL), the enzyme metabolizing 2-AG, robustly reduced protein expression of beta-site APP cleaving enzyme 1 (BACE1), the key enzyme for A-beta synthesis, and decreased deposition of A-beta plaques, neuroinflammation and neurodegeneration, and improved synaptic and cognitive function in an animal model of AD. This means that 2-AG likely plays an important role in counteracting pathogenesis and neuropathology of AD. Previous studies demonstrated that expression of BACE1 at protein levels, but not at mRNA levels, is elevated, both in AD human and animals, suggesting that expression of BACE1 is regulated by an epigenetic mechanism at post-transcriptional levels. Our preliminary studies revealed that expression of the noncoding microRNAs targeting BACE1, was significantly down-regulated both in the brains of AD humans and animals, but the expression was returned to the normal control levels when brain 2-AG levels were elevated in APP transgenic AD animals. Thus, we hypothesize that the actions of brain 2-AG signaling in preventing and reducing pathogenesis and neuropathology of AD are through CB1 receptor-dependent regulation of the expression of the specific miRNAs that repress BACE1, resulting in decreases in A-beta production and accumulation, neuroinflammation and degeneration and improvements in synaptic and cognitive function in AD animals. The proposed project will not only provide molecular mechanisms of strengthening 2-AG signaling in preventing or decreasing pathogenesis and neuropathology of AD, but also will open a new area for the development and discovery of novel drugs aimed at preventing and treating AD, or slowing AD progression.