title: Neuroprotective properties of Bcl-w in Alzheimer disease.
abstract: While there is a host of pro-apoptotic stimuli that target neurons in Alzheimer disease (AD), given the chronicity of the disease and the survival of many neurons, those neurons must either avoid or, at minimum, delay apoptotic death signaling. In this study, we investigated Bcl-w, a novel member of the Bcl-2 family that promotes cell survival. In AD, we found increased levels of Bcl-w associated with neurofibrillary pathology and punctate intracytoplasmic structures whereas, in marked contrast, there are only low diffuse levels of Bcl-w in the neuronal cytoplasm of age-matched control cases. Immunoblot analysis confirmed that Bcl-w levels were significantly increased in AD. By electron microscopy, we determined that the increased Bcl-w expression in AD was ultrastructurally localized to mitochondria and neurofibrillary pathology. To investigate the cause and consequence of Bcl-w up-regulation in neurons, we found that fibrillized amyloid-beta led to increased Bcl-w protein levels in M17 human neuroblastoma cells, and that overexpression of Bcl-w significantly protected neurons against staurosporine- and amyloid-beta-induced apoptosis. Taken together, these series of results suggest that Bcl-w may play an important protective role in neurons in the diseased brain and that this aspect could be therapeutically harnessed to afford neuroprotection.
authors.affiliation: Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106, USA. xiongwei.zhu@case.edu
authors.forename: Xiongwei
authors.initials: X
authors.lastname: Zhu
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Osamu
authors.initials: O
authors.lastname: Ogawa
authors.forename: Hyoung-gon
authors.initials: HG
authors.lastname: Lee
authors.forename: Arun K
authors.initials: AK
authors.lastname: Raina
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Siedlak
authors.forename: Peggy L R
authors.initials: PL
authors.lastname: Harris
authors.forename: Hisashi
authors.initials: H
authors.lastname: Fujioka
authors.forename: Shun
authors.initials: S
authors.lastname: Shimohama
authors.forename: Massimo
authors.initials: M
authors.lastname: Tabaton
authors.forename: Craig S
authors.initials: CS
authors.lastname: Atwood
authors.forename: Robert B
authors.initials: RB
authors.lastname: Petersen
authors.forename: George
authors.initials: G
authors.lastname: Perry
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D019610:Cytoprotection / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D011506:Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; C491073:BCL2L2 protein, human; D010446:Peptide Fragments; D011506:Proteins; C075222:amyloid beta-protein (1-42)