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The Journal of Neuroscience, January 24, 2007, 27(4):893-900; doi:10.1523/JNEUROSCI.3524-06.2007
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Neurobiology of Disease
Bim Is Elevated in Alzheimer's Disease Neurons and Is Required for ß-Amyloid-Induced Neuronal Apoptosis
Subhas C. Biswas, Yijie Shi, Jean-Paul G. Vonsattel, Conrad L. Leung, Carol M. Troy, andLloyd A. Greene Department of Pathology, Center for Neurobiology and Behavior and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University College of Physicians and Surgeons, New York, New York 10032
Correspondence should be addressed to Subhas C. Biswas, Department of Pathology, Columbia University College of Physicians and Surgeons, P&S 15-401, 630 West 168th Street, New York, NY 10032. Email: scb34{at}columbia.edu
The molecules that mediate neuron death in Alzheimer's disease (AD) are largely unknown. We report that ß-amyloid (Aß), a death-promoting peptide implicated in the pathophysiology of AD, induces the proapoptotic protein Bcl-2 interacting mediator of cell death (Bim) in cultured hippocampal and cortical neurons. We further find that Bim is an essential mediator of Aß-induced neurotoxicity. Our examination of postmortem AD human brains additionally reveals upregulation of Bim in vulnerable entorhinal cortical neurons, but not in cerebellum, a region usually unaffected by AD. Accumulating evidence links inappropriate induction/activation of cell cycle-related proteins to AD, but their roles in the disease have been unclear. We find that the cell cycle molecule cyclin-dependent kinase 4 (cdk4) and its downstream effector B-myb, are required for Aß-dependent Bim induction and death in cultured neurons. Moreover, neurons that overexpress Bim in AD brains also show elevated levels of the cell cycle-related proteins cdk4 and phospho-Rb. Our observations indicate that Bim is a proapoptotic effector of Aß and of dysregulated cell cycle proteins in AD and identify both Bim and cell cycle elements as potential therapeutic targets.
Key words: neuronal apoptosis; BH3 only; cell cycle; Alzheimer's disease; Bim; Aß peptide
Received March 24, 2006; revised Dec. 12, 2006; accepted Dec. 15, 2006.
Correspondence should be addressed to Subhas C. Biswas, Department of Pathology, Columbia University College of Physicians and Surgeons, P&S 15-401, 630 West 168th Street, New York, NY 10032. Email: scb34{at}columbia.edu
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