病理生理学：A阝40~42酶解产生过程 APP:110~140kDl,在神经元和胶质细胞上表达 生理功能？ 蛋白水解酶： B、Y、o KPI OX-2 APP-770 Cytoplasmic APP-751 side AB APP-695 Cysteine-rich domain Proteolytic cleavage sites EVKM DAEFRHDSGYEVHHOKLVFFAEDVGSNKGAIIGLMVGGVVIA TVIVITLVMLKKKO.. ZI NL FG,I Swedish double mutation 717"Mutations
病理生理学： Aβ40 ~42 酶解产生过程 APP ： 110~140 kDal，在神经元和胶质细胞上表达 生理功能？ 蛋白水解酶： b、 g 、 a
FAD“Swedish” L670/671 FAD V717 Kunitz protease Ox-2 antigen mutation mutations inhibitor domain domain B N APP770 289345364 62 Stimulated by acetylcholine through muscarinic receptor o-secretase B-secretase Favored when lipid raft too large APPa APPB NEXIN May be modulated ？To establish Y-secretase by certain NSAIDs y-secretase to eliminate production new connections of Abl-42 Free-radical generator To remove old synapses P3 1-40(bad) AB 142(badl)
Stimulated by acetylcholine through muscarinic receptor Favored when lipid raft too large Lipid raft Formed by cholesterol Transported by ApoE From macroglia intracellular extra cellular NEXIN ? To establish new connections ? Free-radical generator ? To remove old synapses
Axon MAM Upregulation EM -AB AB Cell Surface S1R- ER Activation MAM MAM Mitochondria 线粒体相关内质 S1R- Inactivation 网膜 (MAMs)〉 MAM Downregulation 的脂筏上切割 MAM Upregulation-AB Increase AB S1R- 1986,Rudolph Tanzi ActivationT MAM PaIAPP->AB S1R S1R- Inactivation MAM Downregulation-AB Decrease MAM:Mitochondria-Associated ER-Membrane S1R:Sigma-1 Receptor Bhattacharyya,R.,et,al.(2021).Axonal generation of amyloid-B palAPP:Palmitoylated APP from palmitoylated APP in mitochondria-associated endoplasmic EM:Extracellular Matrix reticulum membranes.Cell Reports,35(7),109134. 13
13 线粒体相关内质 网膜（MAMs） 的脂筏上切割 1986，Rudolph Tanzi Bhattacharyya, R., et, al. (2021). Axonal generation of amyloid-β from palmitoylated APP in mitochondria-associated endoplasmic reticulum membranes. Cell Reports, 35(7), 109134
家族性AD的presenilin1和APP突变（红色） Exon 5 o B secretase Exon 4 APP-NTF●R⑦Be0SevKub E T 9 a secretase Y Exon 16 Exon 7 Exon 17 APP G E Exon 6 G Lumen A Exon 11 Exon 7 Exon 12 Exon L A日 -CTF Exon 11 F Exon 9 Cytosol G Exon 10 Exon 6 Exon 8 R Exon 5 A PS1 L L 06000000o0000a Presenilina Exon 9 8 Exon 10 L 0 PS1-CTF e A D Exon 4 Exon 3 PS1-NTF S0000060B00000b80000 000000000000w4 presenilin1的部分y-分泌酶活性（膜相关蛋白水解）
家族性AD 的presenilin 1 和 APP 突变（红色） presenilin 1 的部分g-分泌酶活性（膜相关蛋白水解）
presenilin'sg-分祕酶活性：Notch信号 Lumen or Extracellular Space 8Notch APP剪辑 (“side effect”) TACE cleavage site N APP Presenilin B-secretase cleavage site D 0000 Cytoplasm Y-secretase?
presenilin’s g-分泌酶活性:Notch 信号 APP 剪辑（“side effect”）