Alzheimer Aβ inhibition of eg5/kin5 reduces neurotrophin/transmitter receptor function

The mechanism by which Aβ causes neuronal dysfunction/death in Alzheimer’s disease is unclear. Previously, we showed that Aβ 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 Aβ 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 Aβ or the Kin5 inhibitor monastrol, or expressing APP. Aβ and monastrol also inhibit NGF-dependent neurite outgrowth from PC12 cells and glutamate-dependent Ca++ entry into primary neurons. Like Aβ, monastrol inhibits long-term potentiation, a cellular model of NMDA-dependent learning and memory, and Kin5 activity is absent from APP/PS transgenic mice brain or neurons treated with Aβ. These data imply that cognitive deficits in AD may derive in part from inhibition of neuronal Eg5 by Aβ, resulting in impaired neuronal function/survival through receptor mis-localization. Preventing inhibition of Eg5 or other motors by Aβ may represent a novel approach to Alzheimer’s disease therapy.