Bim is elevated in Alzheimer's disease neurons and is required for beta-amyloid-induced neuronal apoptosis.
The molecules that mediate neuron death in Alzheimer's disease (AD) are largely unknown. We report that beta-amyloid (Abeta), 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 Abeta-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 Abeta-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 Abeta and of dysregulated cell cycle proteins in AD and identify both Bim and cell cycle elements as potential therapeutic targets.
Biswas
Subhas C
SC
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, USA. scb34@columbia.edu
Shi
Yijie
Y
Vonsattel
Jean-Paul G
JP
Leung
Conrad L
CL
Troy
Carol M
CM
Greene
Lloyd A
LA
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000502:physiology* / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D000072224:Bcl-2-Like Protein 11; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D051381:Rats
D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606778:Bcl2l11 protein, rat; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins