title: Alteration of caspases and apoptosis-related proteins in brains of patients with Alzheimer's disease.
abstract: Dysregulated programmed cell death or apoptosis is suggested to be involved in the pathogenesis of Alzheimer's disease (AD). Caspases, the major effectors of apoptosis, are cysteine proteases that cleave crucial substrate proteins exclusively after aspartate residues. The activity of caspases are delicately regulated by a variety of proteins that possess distinct domains for protein-protein interaction. To further substantiate the role of apoptosis in AD, we investigated the levels of nine different proteins involved in apoptosis by Western blot technique in frontal cortex and cerebellum of control and AD subjects. The protein levels of caspase-3, -8, and -9, DFF45 (DNA fragmentation factor 45), and FLIP (Fas associated death domain (FADD)-like interleukin-1beta-converting enzyme inhibitory proteins) were decreased, whereas those of ARC (apoptosis repressor with caspase recruitment domain) and RICK (Receptor interacting protein (RIP)-like interacting CLARP kinase) increased in AD. In contrast, cytochrome c and Apaf-1 (apoptosis protease activating factor-1) were unchanged. Regression analysis revealed no correlation between levels of protein and postmortem interval. However, inconsistent correlation was found between age and levels of proteins as well as among the levels of individual proteins. The current findings showed that dysregulation of apoptotic proteins indeed exists in AD brain and support the notion that it may contribute to neuropathology of AD. The study further hints that apoptosis in AD may occur via the death receptor pathway independent of cytochrome c. Hence, therapeutic strategies that ablate caspase activation may be of some benefit for AD sufferers.
authors.affiliation: Department of Pediatrics, University of Vienna, Vienna, Austria.
authors.forename: E
authors.initials: E
authors.lastname: Engidawork
authors.forename: T
authors.initials: T
authors.lastname: Gulesserian
authors.forename: B C
authors.initials: BC
authors.lastname: Yoo
authors.forename: N
authors.initials: N
authors.lastname: Cairns
authors.forename: G
authors.initials: G
authors.lastname: Lubec
mesh_terms: D000367:Age Factors; D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D053477:Apoptotic Protease-Activating Factor 1; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000096:biosynthesis; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000096:biosynthesis*; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000096:biosynthesis; D003574:Cytochrome c Group / Q000378:metabolism; D005260:Female; D006801:Humans; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009124:Muscle Proteins / Q000096:biosynthesis; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D012044:Regression Analysis
chemical_list: C506592:APAF1 protein, human; D051017:Apoptosis Regulatory Proteins; D053477:Apoptotic Protease-Activating Factor 1; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D015853:Cysteine Proteinase Inhibitors; D003574:Cytochrome c Group; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; C112246:NOL3 protein, human; D011506:Proteins; C109664:caspase-activated DNase inhibitor; D011494:Protein Kinases; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases