Neuroprotective properties of Bcl-w in Alzheimer disease.
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.
Zhu
Xiongwei
X
Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106, USA. xiongwei.zhu@case.edu
Wang
Yang
Y
Ogawa
Osamu
O
Lee
Hyoung-gon
HG
Raina
Arun K
AK
Siedlak
Sandra L
SL
Harris
Peggy L R
PL
Fujioka
Hisashi
H
Shimohama
Shun
S
Tabaton
Massimo
M
Atwood
Craig S
CS
Petersen
Robert B
RB
Perry
George
G
Smith
Mark A
MA
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
D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; C491073:BCL2L2 protein, human; D010446:Peptide Fragments; D011506:Proteins; C075222:amyloid beta-protein (1-42)