Alzheimer amyloid beta inhibition of Eg5/kinesin 5 reduces neurotrophin and/or transmitter receptor function.

ABSTRACT: The mechanism by which amyloid beta (A?) causes neuronal dysfunction and/or death in Alzheimer's disease (AD) is unclear. Previously, we showed that A? inhibits several microtubule-dependent kinesin motors essential for mitosis and also present in mature neurons. Here, we show that inhibition of kinesin 5 (Eg5) by A? blocks neuronal function by reducing transport of neurotrophin and neurotransmitter receptors to the cell surface. Specifically, cell-surface NGF/NTR(p75) and NMDA receptors decline in cells treated with A? or the kinesin 5 inhibitor monastrol, or expressing APP. A? and monastrol also inhibit NGF-dependent neurite outgrowth from PC12 cells and glutamate-dependent Ca++ entry into primary neurons. Like A?, monastrol inhibits long-term potentiation, a cellular model of NMDA-dependent learning and memory, and kinesin 5 activity is absent from APP/PS transgenic mice brain or neurons treated with A?. These data imply that cognitive deficits in AD may derive in part from inhibition of neuronal Eg5 by A?, resulting in impaired neuronal function and/or survival through receptor mislocalization. Preventing inhibition of Eg5 or other motors by A? may represent a novel approach to AD therapy.

SUBMITTER: Ari C 

PROVIDER: S-EPMC4084549 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature