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The Journal of Neuroscience, October 25, 2006, 26(43):10949-10957; doi:10.1523/JNEUROSCI.2793-06.2006

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Neurobiology of Disease
DNA Polymerase- Is Expressed Early in Neurons of Alzheimer's Disease Brain and Is Loaded into DNA Replication Forks in Neurons Challenged with -Amyloid

Agata Copani,^1,3 Jeroen J. M. Hoozemans,⁶ Filippo Caraci,¹ Marco Calafiore,¹ Elise S. Van Haastert,⁶ Robert Veerhuis,⁷ Annemieke J. M. Rozemuller,⁶ Eleonora Aronica,⁶ Maria Angela Sortino,² and Ferdinando Nicoletti^4,5

Departments of ¹Pharmaceutical Sciences and ²Experimental and Clinical Pharmacology, University of Catania, 95125 Catania, Italy, ³Institute of Biostructure and Bioimaging, National Research Council, 95125 Catania, Italy, ⁴Department of Human Physiology and Pharmacology, University of Rome "La Sapienza," 00185 Rome, Italy, ⁵Mediterranean Neurological Institute Neuromed, 86077 Pozzilli, Italy, ⁶Department of Neuropathology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands, and ⁷Departments of Psychiatry, Pathology, and Clinical Chemistry and Alzheimer Center, Vrije University Medical Center, 1007 MB Amsterdam, The Netherlands

Correspondence should be addressed to Dr. Agata Copani, Department of Pharmaceutical Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy. Email: acopani{at}katamail.com

Cultured neurons exposed to synthetic -amyloid (A) fragments reenter the cell cycle and initiate a pathway of DNA replication that involves the repair enzyme DNA polymerase- (DNA pol-) before undergoing apoptotic death. In this study, by performing coimmunoprecipitation experiments on cross-linked nucleoprotein fragments from A-treated neurons, we demonstrate that DNA pol- coimmunoprecipitates with cell division cycle 45 (Cdc45) and with DNA primase in short nucleoprotein fragments. This indicates that DNA pol- is loaded into neuronal DNA replication forks after A treatment. In response to A the canonical DNA-synthesizing enzyme DNA pol- also was loaded into neuronal replication forks, but at later times than DNA pol-. Methoxyamine, an inhibitor of the apurinic/apyrimidinic endonuclease that allows for the recruitment of DNA pol- during the process of base excision repair (BER), failed to affect coimmunoprecipitation between DNA pol- and Cdc45, indicating that DNA pol- loading to the replication forks is independent of DNA breaks. However, methoxyamine reduced DNA replication and ensuing apoptosis in neurons exposed to A, suggesting that an efficient BER process allows DNA replication to proceed up to the threshold for death.

These data demonstrate that DNA pol- is an essential component of the DNA replication machinery in A-treated neurons and additionally support the hypothesis of a close association of cell cycle events with neuronal death in Alzheimer's disease (AD). Accordingly, by investigating the neuronal expression of DNA pol-, along with phosphorylated retinoblastoma protein and neurofibrillary changes in AD brain, we show an early involvement of DNA pol- in the pathogenesis of AD.

Key words: -amyloid; DNA polymerase-; APE-1/Ref-1; methoxyamine; DNA replication; DNA repair

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Received April 14, 2006; revised Aug. 25, 2006; accepted Aug. 29, 2006.

Correspondence should be addressed to Dr. Agata Copani, Department of Pharmaceutical Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy. Email: acopani{at}katamail.com

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