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

NEUROBIOLOGY OF AGING

卷:35

Article

Ari, Csilla^1,2  Borysov, Sergiy I.^1,2,3,4  Wu, Jiashin⁵  Padmanabhan, Jaya^1,2  Potter, Huntington^1,2,3,6,7 

[1] Univ S Florida, USF Hlth Byrd Alzheimers Inst, Tampa, FL USA

[2] Univ S Florida, Coll Med, Dept Mol Med, Tampa, FL USA

[3] Univ S Florida, Eric Pfeiffer Suncoast Alzheimers Ctr, Tampa, FL USA

[4] H Lee Moffitt Canc & Res Ctr, Dept Oncol, Tampa, FL USA

[5] Univ S Florida, Coll Med, Dept Mol Pharmacol & Physiol, Tampa, FL USA

[6] Univ Colorado, Dept Neurol, Denver, CO 80202 USA

[7] Univ Colorado, Linda Crnic Inst Syndrome, Denver, CO 80202 USA

关键词: Alzheimer's disease;    Abeta peptide;    Eg5;    Kinesin 5;    Microtubules;    Neurotrophin receptor;    Neurotransmitter receptor;    p75;    NMDA receptor;    Neurite outgrowth;    Neurodegeneration;    Down syndrome;   

DOI  :  10.1016/j.neurobiolaging.2014.02.006

来源: Elsevier

【 摘 要 】

The mechanism by which amyloid beta (A beta) causes neuronal dysfunction and/or death in Alzheimer'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. (C) 2014 Elsevier Inc. All rights reserved.

【 授权许可】

Free