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

作者：Ari Csilla; Borysov Sergiy I; Wu Jiashin; Padmanabhan Jaya; Potter Huntington^*

来源：Neurobiology of Aging, 2014, 35(8): 1839-1849.

DOI：10.1016/j.neurobiolaging.2014.02.006

• Alzheimer%26apos
• s disease
• Abeta peptide
• Eg5
• Kinesin 5
• Microtubules
• Neurotrophin receptor
• Neurotransmitter receptor
• p75
• NMDA receptor
• Neurite outgrowth
• Neurodegeneration
• Down syndrome

The mechanism by which amyloid beta (A beta) causes neuronal dysfunction and/or death in Alzheimer%26apos;s disease (AD) is unclear. Previously, we showed that A beta 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 beta 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 beta or the kinesin 5 inhibitor monastrol, or expressing APP. A beta and monastrol also inhibit NGF-dependent neurite outgrowth from PC12 cells and glutamate-dependent Ca++ entry into primary neurons. Like A beta, 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 beta. These data imply that cognitive deficits in AD may derive in part from inhibition of neuronal Eg5 by A beta, resulting in impaired neuronal function and/or survival through receptor mislocalization. Preventing inhibition of Eg5 or other motors by A beta may represent a novel approach to AD therapy.

• 出版日期2014-8