title: Alzheimer's Amyloid-β Sequesters Caspase-3 in Vitro via Its C-Terminal Tail.
abstract: Amyloid-β (Aβ), the main constituent in senile plaques found in the brain of patients with Alzheimer's disease (AD), is considered as a causative factor in AD pathogenesis. The clinical examination of the brains of patients with AD has demonstrated that caspase-3 colocalizes with senile plaques. Cellular studies have shown that Aβ can induce neuronal apoptosis via caspase-3 activation. Here, we performed biochemical and in silico studies to investigate possible direct effect of Aβ on caspase-3 to understand the molecular mechanism of the interaction between Aβ and caspase-3. We found that Aβ conformers can specifically and directly sequester caspase-3 activity in which freshly prepared Aβ42 is the most potent. The inhibition is noncompetitive, and the C-terminal region of Aβ plays an important role in sequestration. The binding of Aβ to caspase-3 was examined by cross-linking and proteolysis and by docking and all-atom molecular dynamic simulations. Experimental and in silico results revealed that Aβ42 exhibits a higher binding affinity than Aβ40 and the hydrophobic C-terminal region plays a key role in the caspase-Aβ interaction. Overall, our study describes a novel mechanism demonstrating that Aβ sequesters caspase-3 activity via direct interaction and facilitates future therapeutic development in AD.
authors.affiliation: Genomics Research Center, Academia Sinica, Taiwan , 128, Academia Road, Sec. 2, Nankang Dist., Taipei 115, Taiwan.
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Chang
authors.affiliation: Institute for Computational Science and Technology , SBI Building, Quang Trung Software City, Tan Chanh Hiep Ward, District 12, Ho Chi Minh City, Vietnam.
authors.forename: Nguyen Hoang
authors.initials: NH
authors.lastname: Linh
authors.affiliation: Genomics Research Center, Academia Sinica, Taiwan , 128, Academia Road, Sec. 2, Nankang Dist., Taipei 115, Taiwan.
authors.forename: Yao Hsiang
authors.initials: YH
authors.lastname: Shih
authors.affiliation: Genomics Research Center, Academia Sinica, Taiwan , 128, Academia Road, Sec. 2, Nankang Dist., Taipei 115, Taiwan.
authors.forename: Hui-Ming
authors.initials: HM
authors.lastname: Yu
authors.affiliation: Institute of Physics Polish Academy of Sciences , Al. Lotnikow 32/46, 02-668 Warsaw, Poland.
authors.forename: Mai Suan
authors.initials: MS
authors.lastname: Li
authors.affiliation: Genomics Research Center, Academia Sinica, Taiwan , 128, Academia Road, Sec. 2, Nankang Dist., Taipei 115, Taiwan.
authors.forename: Yun-Ru
authors.initials: YR
authors.lastname: Chen
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism*; D053148:Caspase 3 / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D003198:Computer Simulation; D004195:Disease Models, Animal; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma / Q000473:pathology; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology; D058225:Plaque, Amyloid / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics; D016875:tau Proteins / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D016875:tau Proteins; D053148:Caspase 3
keywords: Alzheimer’s disease; amyloid-β; caspase-3; inhibition; interaction