The antineoplastic drug flavopiridol reverses memory impairmentinduced by Amyloid-ß1-42oligomers in mice

The ectopic re-activation of cell cycle in neurons is an early event in the pathogenesis of Alzheimer'sdisease (AD), which could lead to synaptic failure and ensuing cognitive deficits before frank neuronaldeath. Cytostatic drugs that act as cyclin-dependent kinase (CDK) inhibitors have been poorly investigatedin animal models of AD. In the present study, we examined the effects of flavopiridol, an inhibitor ofCDKs currently used as antineoplastic drug, against cell cycle reactivation and memory loss inducedby intracerebroventricular injection of Aß1-42oligomers in CD1 mice. Cycling neurons, scored as NeuN-positive cells expressing cyclin A, were found both in the frontal cortex and in the hippocampus ofA-injected mice, paralleling memory deficits. Starting from three days after A injection, flavopiridol(0.5, 1 and 3 mg/kg) was intraperitoneally injected daily, for eleven days. Here we show that a treatmentwith flavopiridol (0.5 and 1 mg/kg) was able to rescue the loss of memory induced by A1-42,and toprevent the occurrence of ectopic cell-cycle events in the mouse frontal cortex and hippocampus. This isthe first evidence that a cytostatic drug can prevent cognitive deficits in a non-transgenic animal modelof AD.