北大神经生物学神经系统退行性疾病基础ppt课件

1、 Immunoblotting analysis, immunocytochemical staining and double immunostaining in AD brainOyagi, Asahara, Chui et al. FASEB J. 2005Oyagi, Asahara, Chui et al. FASEB J. 2005崔德华崔德华 DH Chui DH ChuiSummary (3)Intracellular A42 directly activated the p53 promoter resulting in p53-dependent apoptosis.Rem

2、arkably, 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. Intracellular A42 may cause p53-dependent neuronal apoptosis through activation of the p53 promot

3、er; thus demonstrating an alternative pathogenesis in AD.Oyagi, Asahara, Chui et al. FASEB J. 2005Oyagi, Asahara, Chui et al. FASEB J. 2005崔德华崔德华 DH Chui DH ChuiStructure of Human GSK3 崔德华崔德华 DH Chui DH ChuiGSK-3a is required for Ab productionCHO-APP695 cells were transfected with GFP or GSK-3a, and

4、 secreted Ab42 崔德华崔德华 DH Chui DH ChuiLithium blocks Ab accumulation in cultured neurons and in the Lithium blocks Ab accumulation in cultured neurons and in the brains of mice overproducing Ab peptidesbrains of mice overproducing Ab peptidesEmbryonic cortical neurons were infected with SFV containin

5、g wild-type APP (APP-WT) or APP-Swedish (KM670/671NL), then treated with LiCl for 24 h. 崔德华崔德华 DH Chui DH Chui崔德华崔德华 DH Chui DH ChuiEffects of GSK-3b on ADEffects of GSK-3b on ADGSK-3boAbNFT formationNeuronal lossSynapse lossMemory lossAktkinesinTau accumulationtauThis suggests that inhibiting GSK-3

6、 is a promising AD therapyp53Axonal transportdegradation崔德华崔德华 DH Chui DH ChuiTherapeutic Approach for Alzheimer Disease崔德华崔德华 DH Chui DH ChuiTherapeutic Approach for Alzheimer Disease1. AD的普通护理、经济、法律2. 中医药治疗 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.中医药治疗崔德华崔德华 DH Chui DH Chu

7、i乙酰胆碱与乙酰胆碱与ADAD1 1中枢乙酰胆碱含量下降、胆碱乙酰化酶中枢乙酰胆碱含量下降、胆碱乙酰化酶ChATChAT、胆碱酯酶、胆碱酯酶 AchEAchE活性降低或乙酰胆碱受体活性降低或乙酰胆碱受体M-AchRM-AchR、N-AchRN-AchR敏感性降低是敏感性降低是 AD AD的主要的主要病理改动之一。病理改动之一。2 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2-42-4层层崔德华崔德华 DH Chui DH ChuiAcetylcholine a) Ach synthesis b) Ach degradation

8、 Tau崔德华崔德华 DH Chui DH ChuiMemory loss-DementiaMemory loss-Dementia崔德华崔德华 DH Chui DH Chui胆碱抑制剂与胆碱抑制剂与ADAD胆碱抑制剂；胆碱抑制剂；安理申安理申DonapezilDonapezil，多奈哌齐，商品名，多奈哌齐，商品名Aricept)Aricept)艾斯能艾斯能(rivastigmine(rivastigmine，利凡斯的明，商品名，利凡斯的明，商品名Exelon)Exelon)加兰他敏加兰他敏galantaminegalantamine，加兰他敏，商品名，加兰他敏，商品名ReminylRemin

9、yl美金刚胺美金刚胺 MemantineMemantine利用药物减轻早期利用药物减轻早期 AD AD 患者的病症是能够的。到患者的病症是能够的。到 2002 2002 年年 1 1 月，月，FDA FDA 已同意了用于提高记忆力和减缓已同意了用于提高记忆力和减缓 AD AD 病情病情开展的药物。开展的药物。乙酰胆碱酯酶的抑制剂，经过抑制中枢突触间隙的乙酰胆碱酯酶的活性，阻止乙酰胆碱乙酰胆碱酯酶的抑制剂，经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AchAch的分解，提高患的分解，提高患者脑中者脑中AchAch的程度的程度AchAch含量降低是含量降低是ADAD主要病理变化之一，可以

10、改善早期主要病理变化之一，可以改善早期ADAD的病症，但并不是针对病因的根治。的病症，但并不是针对病因的根治。 第四种美金刚胺那么是第四种美金刚胺那么是NMDANMDA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呵斥神经细胞的损伤和凋亡，运用集及超载而呵斥神经细胞的损伤和凋亡，运用NMDANMDA受体低亲和性非竞争拮抗剂治疗痴呆，显示了神经维护和提受体低亲和性非竞争拮抗剂治疗痴呆，显示了神经维护和提高胆碱能功能的作用。高胆碱能功能的作用。这些药物已被证明可以改善记忆效果，且副作用更少。

11、遗憾的是，这些药物并非对每个人都有效，而且其疗效这些药物已被证明可以改善记忆效果，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仅限于早期和中期 AD AD 患者。患者。崔德华崔德华 DH Chui DH ChuiADAD的新免疫疗法的新免疫疗法History of passive antibody therapyHistory of passive antibody therapyIn the early 1890s, Behring and Kitasato found that injecting nonlethal doses of tetanus to

12、xin 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.崔德华崔德华 DH Chui DH ChuiInflammation and immune mechanisms in Alzheimers diseaseDennis J. Selkoe NATURE VOL 420 19/26 DECEMBER 2002崔德华崔德华 DH Chui

13、DH ChuiThe A Life Cycle and Possible Points of Therapeutic InterventionsTanzi RE Cell. 2005 25;120 545 Tanzi RE Cell. 2005 25;120 545 崔德华崔德华 DH Chui DH ChuiAdaptive ImmunityCNS as a immune privilege site: blood-brain-barrierB cell and T cell epitope: implication for vaccine崔德华崔德华 DH Chui DH Chui崔德华崔

14、德华 DH Chui DH Chui崔德华崔德华 DH Chui DH ChuiImprove Ab clearance while Improve Ab clearance while avoiding inflammatory effectavoiding inflammatory effect崔德华崔德华 DH Chui DH ChuiWestern blotConfocal: intensity of CD11b IRWTEP2-/-Microglia Lacking E Prostanoid Receptor Subtype 2 Have Enhanced Ab Phagocytos

15、is Yet Lack Ab-activated NeurotoxicityAm J Pathol, Vol. 166, No. 4, 2005Am J Pathol, Vol. 166, No. 4, 2005崔德华崔德华 DH Chui DH ChuiMicroglia lacking E prostanoid receptor subtype 2 have enhanced Ab phagocytosis yet lack Ab-activated neurotoxicity Microglia can be neuroprotective by phagocytosing Ab; 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 Ab peptides from AD brain sections and suppresse