Cellular And Molecular Pathogenesis Of Alzheimer

目前大约有500万美国人患有阿尔茨海默病（AD），这是一种以认知功能进行性损害、情绪和睡眠障碍为特征的神经退行性疾病。本实验室建立了阿尔茨海默病的细胞培养和小鼠模型，并利用这些模型阐明了阿尔茨海默病神经元功能障碍和死亡的生化和分子事件。我们发现AD患者的大脑中存在脂质代谢异常。具体来说，胆固醇和长链神经酰胺的水平会增加。实验动物和AD细胞培养模型的研究表明，与淀粉样蛋白沉积相关的氧化应激增加是脂质异常的原因。抗氧化剂和阻止神经酰胺产生的药物可以保护神经元免受淀粉样蛋白的破坏和杀死，这表明脂质异常在疾病过程中起着重要作用。膜脂过氧化似乎在淀粉样前体蛋白的淀粉样变性过程中起重要作用，因为脂质过氧化产物4-羟基壬烯醛共价修饰蛋白质nicastrin，从而增加γ -分泌酶活性。我们还发现质膜上的氧化还原酶在保护神经元免受膜脂过氧化和β毒性方面发挥重要作用。在其他研究中，我们提供的证据表明，神经元和神经胶质细胞中某些toll样受体（TLRs）的激活使神经元容易受到β毒性和能量剥夺的影响。此外，TLRs 2、3和4在学习记忆和焦虑等行为的调节中具有有趣而不同的作用。其他研究结果表明，在AD患者和健忘轻度认知障碍患者的脑细胞中存在DNA碱基切除修复缺陷。此外，我们发现饮食限制可以减少AD动物模型中的淀粉样蛋白沉积，保护神经元免受损伤和死亡，并且饮食限制的这种有益作用涉及刺激脑源性神经营养因子（BDNF）的产生。抗抑郁5 -羟色胺再摄取抑制剂可以减少淀粉样蛋白沉积并改善AD小鼠模型的认知功能，提示此类药物具有潜在的预防/治疗用途。我们已经证明，糖尿病导致认知功能缺陷，这与海马突触可塑性和神经发生受损有关；运动和限制饮食能量可以抵消糖尿病的这些不利影响。我们最近在糖尿病和阿尔茨海默病的动物模型中展示了用于改善血糖控制的药物的治疗益处，我们正在推进其中一种药物艾塞那肽的临床试验，用于轻度认知障碍或早期阿尔茨海默病的人类受试者。

Approximately 5 million Americans currently suffer from Alzheimers disease (AD) a neurodegenerative disorder characterized by progressive impairment of cognitive function and emotional and sleep disturbances. This laboratory has developed cell culture and mouse models of AD, and have used these models to elucidate the biochemical and molecular events responsible for neuronal dysfunction and death in AD. We have found that there are abnormalities in lipid metabolism in the brains of patients with AD. Specifically, levels of cholesterol and long-chain ceramides are increased. Studies of experimental animal and cell culture models of AD suggest that increased oxidative stress, associated with amyloid deposition is responsible for the lipid abnormalities. Antioxidants and drugs that prevent the production of ceramides protect neurons from being damaged and killed by amyloid suggesting an important role for the lipid abnormalities in the disease process. Membrane lipid peroxidation appears to play an important role in amyloidogenic processing of the amyloid precursor protein as the lipid peroxidation product 4-hydroxynonenal covalently modifies the protein nicastrin and thereby increases gamma-secretase activity. We have also found that redox enzymes in the plasma membrane play important roles in protecting neurons against membrane lipid peroxidation and Abeta toxicity. In other studies we have provided evidence that activation of certain toll-like receptors (TLRs) in neurons and glial cells renders neurons vulnerable to Abeta toxicity and energy deprivation. Moreover,TLRs 2, 3 and 4 have interesting and disparate roles in the regulation of behaviors, including learning and memory and anxiety. Additional findings suggest that there is a defect in DNA base excision repair in brain cells of AD patients and subjects with amnestic mild cognitive impairment. Moreover, we have found that dietary restriction can reduce amyloid deposition and protect neurons from being damaged and killed in animal models of AD, and that this beneficial effect of dietary restriction involves stimulation of the production of brain-derived neurotrophic factor (BDNF). Antidepressant serotonin reuptake inhibitors can reduce amyloid deposition and improve cognitive function in a mouse model of AD, suggesting a potential prophylactic/therapeutic use of such drugs. We have shown that diabetes causes a deficit in cognitive function which is associated with impaired hippocampal synaptic plasticity and neurogenesis; exercise and dietary energy restriction can counteract these adverse effects of diabetes. We recently demonstrated a therapeutic benefit of drugs used to improve glycemic control in animal models of diabetes and Alzheimer's disease, and we are moving forward with a clinical trial of one of these drugs, Exenatide, in human subjects with mild cognitive impairment or early stage Alzheimer's disease.