title: Gamma secretase-activating protein is a substrate for caspase-3: implications for Alzheimer's disease.
abstract: BACKGROUND
  A major feature of Alzheimer's disease (AD) is the accumulation of amyloid-beta (Aβ), whose formation is regulated by the gamma-secretase complex and its activating protein (also known as GSAP). Because GSAP interacts with gamma-secretase without affecting the cleavage of Notch, it is an ideal target for a viable anti-Aβ therapy. However, despite much interest in this protein, the mechanisms involved in its neurobiology are unknown.
  
  
  METHODS
  Postmortem brain tissue samples from AD patients, transgenic mouse models of AD, and neuronal cells were used to investigate the molecular mechanism involved in GSAP formation and subsequent amyloidogenesis.
  
  
  RESULTS
  We identified a caspase-3 processing domain in the GSAP sequence and provide experimental evidence that this caspase is essential for GSAP activation and biogenesis of Aβ peptides. Furthermore, we demonstrated that caspase-3-dependent GSAP formation occurs in brains of individuals with AD and two different mouse models of AD and that the process is biologically relevant because its pharmacological blockade reduces Aβ pathology in vivo.
  
  
  CONCLUSIONS
  Our data, by identifying caspase-3 as the endogenous modulator of GSAP and Aβ production, establish caspase-3 as a novel, attractive and viable Aβ-lowering therapeutic target for AD.
authors: Department of Pharmacology, Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania.
authors: Jin
authors: J
authors: Chu
authors: Department of Pharmacology, Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania.
authors: Jian-Guo
authors: JG
authors: Li
authors: Department of Pharmacology, Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania.
authors: Yash B
authors: YB
authors: Joshi
authors: Department of Pharmacology, Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania.
authors: Phillip F
authors: PF
authors: Giannopoulos
authors: Department of Pharmacology, Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania.
authors: Nicholas E
authors: NE
authors: Hoffman
authors: Department of Pharmacology, Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania.
authors: Muniswamy
authors: M
authors: Madesh
authors: Department of Pharmacology, Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania. Electronic address: praticod@temple.edu.
authors: Domenico
authors: D
authors: Praticò
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016296:Mutagenesis; D009154:Mutation; D009447:Neuroblastoma / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C552289:GSAP protein, human; C508853:PSEN1 protein, human; D053764:Presenilin-1; D011506:Proteins; D034741:RNA, Small Interfering; D053148:Caspase 3
keywords: Alzheimer’s disease; Amyloid beta; Caspase-3; Gamma secretase; Gamma secretase-activating protein; Transgenic mice