Kif11 overexpression rescues cognition, long-term potentiation, and spine defects in mouse and cell models of Alzheimer's disease

Abstract

Competitive inhibition of kinesin motor proteins by amyloid-beta (A{beta}) may contribute to alterations in the neuronal microtubule cytoskeleton that can disrupt plasticity mechanisms required for learning and memory, such as long-term potentiation (LTP), thus contributing to synaptic dysfunction and cognitive impairments associated with Alzheimers disease (AD). Here, we tested the hypothesis that overexpression of the microtubule motor protein KIF11 (Kinesin-5/Eg5) will rescue A{beta}-mediated synaptic dysfunction and cognitive impairments. We found that overexpression of Kif11 prevented spatial learning and LTP deficits in the 5xFAD mouse model of AD and rescued A{beta}-mediated decreases in postsynaptic dendritic spine density in neuronal cultures. Together, these data suggest that KIF11 function is important for preserving synaptic structures and functions that are critical for learning and memory and for protection against A{beta}-mediated loss of cognition in AD. HighlightsO_LIDeficits in cognition and long-term potentiation in the 5xFAD mouse model of Alzheimers disease are prevented by Kif11 overexpression. C_LIO_LIA{beta}-mediated dendritic spine loss is blocked by Kif11 overexpression. C_LI