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Uncovering first molecular missteps that drive neurons in pathway leading to Alzheimer's disease
Date:12/15/2013

Much of the debate in Alzheimer's disease (AD) has focused on whether the protein amyloid-beta or the tau protein is the symptom or the cause of the disease.

But George Bloom, Ph.D., and colleagues at the University of Virginia (UVA) have pursued another hypothesis: much earlier interactions between the two proteins them drive adult neurons into the forbidden pathway of "cell cycle re-entry" (CCR).

Dr. Bloom will present additional evidence supporting the role of CCR in AD on Sunday, Dec. 15, at the American Society for Cell Biology (ASCB) annual meeting in New Orleans. He will report the identification of a critical balance point between tau and a master cellular regulator that amyloid-beta oligomers disrupt.

A novel group of proteins, Rac1, Gαs (Gs alpha) and NCAM, and two protein kinase complexes, mTORC1 and mTORC2, play a role in driving mature neurons to their death, according to the UVA researchers.

These new findings are scientific sequels to a series of dramatic discoveries by the Dr. Bloom's lab that unravel the molecular events that drive adult neurons in CCR. As Dr. Bloom noted in his research presentation at last year's ASCB annual meeting, most normal adult neurons are supposed to be permanently post-mitotic -- that is, they have finished dividing and are locked out of the cell cycle.

Yet in AD, neurons frequently re-enter the cell cycle, fail to complete mitosis and ultimately die. In late stage AD, up to 30 percent of the neurons in the frontal lobes of the brain are dead, surrounded by large amyloid plaques and tau-associated neurofibrillary tangles.

Dr. Bloom said that he views AD as fundamentally a problem of the cell cycle, with both amyloid-beta and tau required for the interaction that pushes neurons into destructive CCR. "The massive neuron death that occurs in AD therefore appears to be caused by the raw ingredients of plaques and tangles working in concert with each other, r
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Contact: Cathy Yarbrough
cyarbrough@ascb.org
858-243-1814

John Fleischman
jfleischman@ascb.org

American Society for Cell Biology
Source:Eurekalert


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