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The Journal of Neuroscience, October 22, 2008, 28(43):10786-10793; doi:10.1523/JNEUROSCI.2441-08.2008

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Neurobiology of Disease
Aβ Oligomers Induce Neuronal Cell Cycle Events in Alzheimer's Disease

Nicholas H. Varvel,^1,2 * Kiran Bhaskar,^1 * Anita R. Patil,¹ Sanjay W. Pimplikar,¹ Karl Herrup,⁴ and Bruce T. Lamb^1,2,3

¹Department of Neurosciences, NC30, Lerner Research Institute, The Cleveland Clinic, Cleveland, Ohio 44195-0001, Departments of ²Neurosciences and ³Genetics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4955, and ⁴Department of Cell Biology and Neuroscience, Nelson Biological Laboratories, Rutgers, The State University of New Jersey, Busch Campus, Piscataway, New Jersey 08854-8082

Correspondence should be addressed to Bruce T. Lamb, Department of Neurosciences, NC30, Lerner Research Institute, The Cleveland Clinic, NC3-164, 9500 Euclid Avenue, Cleveland, OH 44195-0001. Email: lamb{at}ccf.org

Neurons subject to degeneration in Alzheimer's disease (AD) exhibit evidence of re-entry into a mitotic cell cycle even before the development of substantial AD brain pathology. In efforts to identify the initiating factors underlying these cell cycle events (CCEs), we have characterized the appearance of the neuronal CCEs in the genomic-based R1.40 transgenic mouse model of AD. Notably, R1.40 mice exhibit neuronal CCEs in a reproducible temporal and spatial pattern that recapitulates the neuronal vulnerability seen in human AD. Neuronal CCEs first appear at 6 months in the frontal cortex layers II/III. This is 6–8 months before detectable amyloid β (Aβ) deposition, suggesting that specific amyloid precursor protein (APP) processing products are responsible for the induction of neuronal CCEs. Furthermore, a reduction in the levels of Aβ (achieved by shifting the genetic background from C57BL/6 to the DBA/2 mouse strain) dramatically delays the appearance of neuronal CCEs. More significantly, elimination of β-secretase activity blocks the appearance of CCEs, providing direct genetic evidence that the amyloidogenic processing of APP is required for the induction of CCEs. Finally, in vitro preparations of oligomeric, but not monomeric, Aβ induce DNA synthesis in dissociated cortical neurons, and this response is blocked by antioligomer specific antibodies. Together, our data suggest that low molecular weight aggregates of Aβ induce neuronal cell cycle re-entry in mouse models of Alzheimer's disease.

Key words: Alzheimer's disease; APP; β-amyloid; neuronal cell cycle; cyclin A; transgenic mice

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Received May 30, 2008; revised Aug. 4, 2008; accepted Sept. 6, 2008.

Correspondence should be addressed to Bruce T. Lamb, Department of Neurosciences, NC30, Lerner Research Institute, The Cleveland Clinic, NC3-164, 9500 Euclid Avenue, Cleveland, OH 44195-0001. Email: lamb{at}ccf.org

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