Format

Send to

Choose Destination
Neurobiol Aging. 2014 Aug;35(8):1839-49. doi: 10.1016/j.neurobiolaging.2014.02.006. Epub 2014 Feb 10.

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

Author information

1
USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, FL, USA; Department of Molecular Medicine, College of Medicine, University of South Florida, Tampa, FL, USA.
2
USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, FL, USA; Department of Molecular Medicine, College of Medicine, University of South Florida, Tampa, FL, USA; Eric Pfeiffer Suncoast Alzheimer's Center, University of South Florida, Tampa, FL, USA; Department of Oncology, H. Lee Moffitt Cancer and Research Center, Tampa, FL, USA.
3
Department of Molecular Pharmacology and Physiology, College of Medicine, University of South Florida, Tampa, FL, USA.
4
USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, FL, USA; Department of Molecular Medicine, College of Medicine, University of South Florida, Tampa, FL, USA; Eric Pfeiffer Suncoast Alzheimer's Center, University of South Florida, Tampa, FL, USA; Department of Neurology and Linda Crnic Institute for Down Syndrome, Anschutz Medical Campus, University of Colorado, Denver, Aurora, CO, USA. Electronic address: Huntington.Potter@UCDenver.edu.

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.

KEYWORDS:

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

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center