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,#1
* Biochemistry and
Pharmacology, School of Medicine, University of Catania, 95125 Catania;
Institute of Respiratory Disease, Ospedale Tomaselli, 95125 Catania, Italy;
§ Consorzio Mario Negri Sud, 66030 S. Maria Imbaro, Chieti, Italy;
¶ Department Internal Medicine and Medical Therapy, University of Pavia, 27100 Pavia, Italy;
Department of Pharmaceutical Sciences, School of Pharmacy, University of Catania, 95125 Catania;
# I. N. M. Neuromed, Localita‘ Camerelle, 86077 Pozzilli, Isernia, Italy
1Correspondence: Department of Pharmaceutical Sciences, Section of Pharmacology, School of Pharmacy, University of Catania, Viale A. Doria 6, 95125 Catania, Italy. E-mail: nicoletti.ferdinando{at}ctonline.it
Aggregates of ß-amyloid peptide (ßAP), the main constituent of amyloid plaques in Alzheimer’s brain, kill neurons by a not yet defined mechanism, leading to apoptotic death. Here, we report that both full-length ßAP(1–40) or (1–42) and its active fragment ßAP(25–35) act as proliferative signals for differentiated cortical neurons, driving them into the cell cycle. The cycle followed some of the steps observed in proliferating cells, including induction of cyclin D1, phosphorylation of retinoblastoma, and induction of cyclin E and A, but did not progress beyond S phase. Inactivation of cyclin-dependent protein kinase-4 or -2 prevented both the entry into S phase and the development of apoptosis in ßAP(25–35)-treated neurons. We conclude that neurons must cross the G1/S transition before succumbing to ßAP signaling, and therefore multiple steps within this pathway may be targets for neuroprotective agents.—Copani, A., Condorelli, F., Caruso, A., Vancheri, C., Sala, A., Giuffrida Stella, A. M., Canonico, P. L., Nicoletti, F., Sortino, M. A. Mitotic signaling by ß-amyloid causes neuronal death.
Key Words: neuronal apoptosis • cell cycle • Alzheimer’s disease.
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