The cell cycle molecules behind neurodegeneration in Alzheimer's disease: perspectives for drug development.
Alzheimer's disease (AD), the leading cause of senile dementia, has become a considerable social and economical problem. Current AD therapeutics provide mainly symptomatic short-term benefit, rather than targeting disease mechanisms. The hallmarks for AD are beta-amyloid plaques, neurofibrillary tangles, and regionalized neuronal loss. Additional neuropathological features have been described that may provide some clues to the mechanism by which neurons die in AD. Specifically, the aberrant expression of cell cycle proteins and the presence of de novo-replicated DNA in neurons have been described both in AD brain and in culture models of the disease. The unscheduled cell cycle events are deleterious to neurons, which undergo death rather than complete the cell cycle. Although our understanding of the neuronal cell cycle is not complete, experimental evidence suggests that compounds able of arresting the aberrant cell cycle will yield neuroprotection. This review focuses on drug development centered on the cell cycle hypothesis of AD.
Copani
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Department of Pharmaceutical Sciences, CNR-Catania, Catania, Italy. acopani@katamail.com
Guccione
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Giurato
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Caraci
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Calafiore
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Nicoletti
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D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008959:Models, Neurological; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use
D018696:Neuroprotective Agents