Neuroprotective properties of Bcl-w in Alzheimer disease

Xiongwei Zhu, Yang Wang, Osamu Ogawa, Hyoung Gon Lee, Arun K. Raina, Sandra L. Siedlak, Peggy L.R. Harris, Hisashi Fujioka, Shun Shimohama, Massimo Tabaton, Craig S. Atwood, Robert B. Petersen, George Perry, Mark A. Smith

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

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-β 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-β-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.

Original languageEnglish
Pages (from-to)1233-1240
Number of pages8
JournalJournal of Neurochemistry
Volume89
Issue number5
DOIs
StatePublished - Jun 2004

Keywords

  • Alzheimer disease
  • Amyloid-β
  • Apoptosis Bcl-w
  • Neuroprotection
  • Signal transduction

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