Amyloid beta peptide binds a novel death-inducing protein, AB-DIP.
Amyloid beta-peptide (Abeta) plays a central role in the pathogenesis of Alzheimer's disease (AD). It is toxic to neurons, but the mechanism for its action remains largely unknown. Here, we have identified a novel death-inducing protein, Abeta-related DIP (AB-DIP), by two-hybrid screening of the human brain cDNA library and confirmed the binding of Abeta with AB-DIP by coimmunoprecipitation. Overexpression of AB-DIP-induced cell death and coexpression of Abeta enhanced the cell death. During apoptosis, the 97-kDa AB-DIP was cleaved to a 62-kDa protein (AB-DIP p62) at the caspase cleavage site, LEKD. It is more important that cotransfection of Abeta with AB-DIP produced the AB-DIP p62 fragment. Small interfering RNA-mediated knockdown of AB-DIP protein expression significantly protected neuroblastoma cells from Abeta-induced neurotoxicity. AB-DIP may mediate the neurotoxicity of Abeta, and therefore, AB-DIP may be a potential, therapeutic target for AD.
Lakshmana
Madepalli K
MK
Department of Vascular Dementia Research, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan. laxman@nils.go.jp
Araki
Wataru
W
Tabira
Takeshi
T
D000544:Alzheimer Disease / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D017304:Annexin A5 / Q000032:analysis; D017209:Apoptosis; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D047468:Immunoprecipitation; D024101:Mitochondrial Proteins / Q000032:analysis / Q000502:physiology*; D009447:Neuroblastoma / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D020798:Two-Hybrid System Techniques
D016229:Amyloid beta-Peptides; D017304:Annexin A5; C503369:GRAMD4 protein, human; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases