Elevated expression of a regulator of the G2/M phase of the cell cycle, neuronal CIP-1-associated regulator of cyclin B, in Alzheimer's disease.

Abstract

Adult neurons are generally accepted to be in a quiescent, nonproliferative state. However, it is becoming increasingly apparent that, in Alzheimer's disease (AD), alterations in cell cycle machinery, suggesting an attempt to reenter cell cycle, relate temporally and topographically to degenerating neurons. These findings, together with the fact that neurons lack the necessary components for completion of mitosis, have led to the notion that an ill-regulated attempt to reenter the cell cycle is associated with disease pathogenesis and, ultimately, neuronal degeneration. To understand better the role of such cell cycle abnormalities in AD, we undertook a study of CIP-1-associated regulator of cyclin B (CARB), a protein that associates with two key proteins, p21 and cyclin B, involved in cellular checkpoints in the cell cycle. Our results show that there are increases in CARB localized to intraneuronal neurofibrillary tangles and granulovacuolar degeneration in susceptible hippocampal and cortical neurons in AD. By marked contrast, CARB is found only at background levels in these neuronal populations in nondiseased age-matched controls. Our data not only provide another line of evidence indicative of cell cycle abnormalities in neurons in AD but also lend further credence to the hypothesis that susceptible neurons may be arrested at the G2/M phase of the cell cycle before they die. Therefore, therapeutics targeted toward initiators of the cell cycle are likely to prove of great efficacy for the treatment of AD.

• Authors: Xiongwei Zhu, Andrew McShea, Peggy L R Harris, Arun K Raina, Rudy J Castellani, Jens Oliver Funk, Sapan Shah, Craig Atwood, Richard Bowen, Robert Bowser, Laura Morelli, George Perry, Mark A Smith
• Journal: Journal of neuroscience research (J Neurosci Res) Vol. 75 Issue 5 Pg. 698-703 (Mar 01 2004) ISSN: 0360-4012 [Print] United States
• PMID: 14991845 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2004 Wiley-Liss, Inc.

Chemical References

• CCNB1 protein, human
• CDKN1A protein, human
• Carrier Proteins
• Cell Cycle Proteins
• Cyclin B
• Cyclin B1
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclins
• Nerve Tissue Proteins

Topics

• Aged
• Aged, 80 and over
• Alzheimer Disease (metabolism, pathology)
• Carrier Proteins (metabolism)
• Cell Cycle Proteins (metabolism)
• Cyclin B (metabolism)
• Cyclin B1
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclins (metabolism)
• Female
• G2 Phase (physiology)
• Hippocampus (metabolism, pathology)
• Humans
• Immunohistochemistry
• Male
• Matched-Pair Analysis
• Middle Aged
• Mitosis (physiology)
• Neocortex (metabolism, pathology)
• Nerve Tissue Proteins (metabolism)
• Neurofibrillary Tangles (metabolism)
• Neurons (metabolism, pathology)
• Reference Values