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The Journal of Neuroscience, January 18, 2006, 26(3):775-784; doi:10.1523/JNEUROSCI.3707-05.2006
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Neurobiology of Disease
Ectopic Cell Cycle Events Link Human Alzheimer's Disease and Amyloid Precursor Protein Transgenic Mouse Models
Yan Yang,1 * Nicholas H. Varvel,2,4 * Bruce T. Lamb,2,3,4 andKarl Herrup1,2 1Department of Neurology, University Hospitals of Cleveland, Departments of 2Neurosciences and 3Genetics, Case Western Reserve University, Cleveland, Ohio 44106, and 4Department of Neurosciences, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195
Nerve cells that re-enter a cell cycle will die rather than divide, a fact that likely underlies the neurodegeneration in Alzheimer's disease (AD). Several mouse models of familial AD have been created, and although many display amyloid plaques in their brains, none captures the extensive pattern of nerve cell death found in the human disease. Using both immunocytochemistry and fluorescent in situ hybridization, we show that neurons in three different mouse models reproduce the ectopic cell cycling found in human AD. The temporal and spatial appearance of the cell cycle events in the mouse closely mimics the human disease progression. The cell-cycle events are evident 6 months before the first amyloid deposits and significantly precede the appearance of the first CD45+ microglia. These data suggest that the ectopic initiation of cell-cycle processes in neurons is an early sign of neuronal distress in both human and mouse AD. The close phenotypic correspondence indicates a previously unsuspected level of fidelity of the mouse model to the human disease. Finally, the relative timing suggests that neither the activated microglia nor the amyloid plaques themselves are necessary to initiate the pathogenic events in AD.
Key words: PCNA; cyclin A; FISH; neuronal death; APP;
-amyloid
Received Sep 1, 2005; revised November 18, 2005; accepted November 22, 2005.
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