医学]北大神经生物学课件6-3神经系统退行性疾病基础.ppt

Immunoblotting analysis, immunocytochemical staining and double immunostaining in AD brain Oyagi, Asahara, Chui et al. FASEB J. 2005崔德华 DH Chui Summary (3) 1. Intracellular A42 directly activated the p53 promoter resulting in p53-dependent apoptosis. Remarkably, accumulation of both A42 and p53 was found in some degenerating-shape neurons in both mice and AD cases. Thus, the intracellular A42/p53 pathway may be directly relevant to neuronal loss in AD. 1. 1. Intracellular AIntracellular A 42 may cause p53-dependent neuronal 42 may cause p53-dependent neuronal apoptosis through activation of the p53 promoter; apoptosis through activation of the p53 promoter; thus demonstrating an alternative pathogenesis in AD.thus demonstrating an alternative pathogenesis in AD. Oyagi, Asahara, Chui et al. FASEB J. 2005崔德华 DH Chui Structure of Human GSK3 崔德华 DH Chui GSK-3a is required for A production CHO-APP695 cells were transfected with GFP or GSK-3a, and secreted Ab42 崔德华 DH Chui Lithium blocks A accumulation in cultured neurons and in the brains of mice overproducing A peptides Embryonic cortical neurons were infected with SFV containing wild-type APP (APP-WT) or APP-Swedish (KM670/671NL), then treated with LiCl for 24 h. 崔德华 DH Chui 崔德华 DH Chui Effects of GSK-3 on AD GSK-3 oA NFT formation Neuronal loss Synapse loss Memory loss Akt kinesin Tau accumulation GSK-3GSK-3 InhibitorInhibitor tau This suggests that inhibiting GSK-3 is a promising AD therapy p53 Axonal transport degradation 崔德华 DH Chui Therapeutic Approach for Alzheimer Disease 崔德华 DH Chui Therapeutic Approach for Alzheimer Disease 1. AD的一般护理、经济、法律 2. 西医药治疗 胆碱酯酶抑制剂疗法 AD的新免疫疗法 抗炎疗法 gama和beta-APP分泌酶抑制剂疗法 GSK-3beta抑制剂疗法 其他 3.中医药治疗 崔德华 DH Chui 乙酰胆碱与ADAD 1）中枢乙酰胆碱含量下降、胆碱乙酰化酶（ChAT）、胆碱酯酶 （AchE ）活性降低或乙酰胆碱受体（M-AchR、N-AchR）敏感性降低是 AD的主要 病理改变之一。 2）胆碱能神经元主要位于纹状体、伏隔核、嗅结节、海马和皮质2-4层 崔德华 DH Chui Acetylcholine a) Ach synthesis b) Ach degradation Tau 崔德华 DH Chui Memory loss-Dementia Alzheimer diseaseAlzheimer disease 崔德华 DH Chui 胆碱抑制剂与ADAD 胆碱抑制剂； 安理申（Donapezil，多奈哌齐，商品名Aricept) 艾斯能(rivastigmine，利凡斯的明，商品名Exelon) 加兰他敏（galantamine，加兰他敏，商品名Reminyl） 美金刚胺 （Memantine） 利用药物减轻早期 AD 患者的症状是可能的。到 2002 年 1 月，FDA 已批准了用于提高记忆力和减缓 AD 病情 发展的药物。 乙酰胆碱酯酶的抑制剂，通过抑制中枢突触间隙的乙酰胆碱酯酶的活性，阻止乙酰胆碱（Ach）的分解，提高患 者脑中Ach的水平（Ach含量降低是AD主要病理变化之一），可以改善早期AD的症状，但并不是针对病因的根治。 第四种美金刚胺则是NMDA受体的拮抗剂，它不仅可拮抗兴奋性氨基酸的兴奋毒性，还可以防止细胞内钙的聚集及 超载而造成神经细胞的损伤和凋亡，应用NMDA受体低亲和性非竞争拮抗剂治疗痴呆，显示了神经保护和提高胆碱 能功能的作用。 这些药物已被证实能够改善记忆效果，且副作用更少。遗憾的是，这些药物并非对每个人都有效，而且其疗效仅 限于早期和中期 AD 患者。 崔德华 DH Chui AD的新免疫疗法 History of passive antibody therapy In the early 1890s, Behring and Kitasato found that injecting nonlethal doses of tetanus toxin into animals causes the animals blood to develop the ability to neutralize the toxin in 1901, von Behring was awarded the first Nobel prize in Medicine. 崔德华 DH Chui Inflammation and immune mechanisms in Alzheimers disease Dennis J. Selkoe NATURE VOL 420 19/26 DECEMBER 2002崔德华 DH Chui The A Life Cycle and Possible Points of Therapeutic Interventions Tanzi RE Cell. 2005 25;120 545 崔德华 DH Chui Adaptive Immunity CNS as a immune privilege site: blood-brain-barrier B cell and T cell epitope: implication for vaccine 崔德华 DH Chui 崔德华 DH Chui 崔德华 DH Chui Improve A clearance while avoiding inflammatory effect 崔德华 DH Chui Western blot Confocal: intensity of CD11b IR WTEP2-/- Microglia Lacking E Prostanoid Receptor Subtype 2 Have Enhanced A Phagocytosis Yet Lack A-activated Neurotoxicity Am J Pathol, Vol. 166, No. 4, 2005崔德华 DH Chui Microglia lacking E prostanoid receptor subtype 2 have enhanced A phagocytosis yet lack A-activated neurotoxicity Microglia can be neuroprotective by phagocytosing A; however, this comes at the cost of activated innate immunity that causes paracrine damage to neurons. Ablation of E prostanoid receptor subtype 2 significantly increased microglial-mediated clearance of A peptides from AD brai