Abstract:
:The mechanism by which amyloid beta (Aβ) causes neuronal dysfunction and/or death in Alzheimer's disease (AD) 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 kinesin 5 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 kinesin 5 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 and/or survival through receptor mislocalization. Preventing inhibition of Eg5 or other motors by Aβ may represent a novel approach to AD therapy.
journal_name
Neurobiol Agingjournal_title
Neurobiology of agingauthors
Ari C,Borysov SI,Wu J,Padmanabhan J,Potter Hdoi
10.1016/j.neurobiolaging.2014.02.006subject
Has Abstractpub_date
2014-08-01 00:00:00pages
1839-49issue
8eissn
0197-4580issn
1558-1497pii
S0197-4580(14)00180-8journal_volume
35pub_type
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