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

Abstract

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.

Inhibition of the Motor Protein Eg5/Kinesin-5 in Amyloid β-Mediated Impairment of Hippocampal Long-Term Potentiation and Dendritic Spine Loss

“…Previous data from our laboratory indicate that both Ab(1-42) and monastrol result in reduced surface levels of NMDAR GluN1 and GluN2B subunits in cultured cells over several days, as measured by flow cytometry and confocal imaging (Ari et al, 2014). However, our data here are not consistent with any acute effect of Ab(1-42) or monastrol on synaptic NMDARs being responsible for LTP inhibition, as 20 minutes of preincubation with Ab(1-42) or monastrol was sufficient to inhibit LTP but had no significant impact on pharmacologically isolated N-methyl-D-aspartate fEPSPs.…”

“…In addition, prolonged exposure to Ab(1-42) or monastrol can also lead to reduced surface expression of AMPAR and NMDAR subunits Ari et al, 2014), perhaps due to both enhanced endocytosis and impaired delivery to the plasma membrane. Given that we observed a small reduction in synaptic NMDAR activity after 1 hour of Eg5 inhibition with monastrol, we next examined the impacts of longer Ab(1-42) and monastrol treatments on the number of dendritic spines in cultured mouse hippocampal neurons as an indicator of synapse loss (Fig.…”

“…Several hypotheses have been posited to explain how Ab inhibits LTP and alters brain function through perturbing various signaling pathways. In this regard Ab can interact with a number of different membrane receptors, including N-methyl-D-aspartate receptors (NMDAR) (Shankar et al, 2007;Kurup et al, 2010;Ari et al, 2014), metabotropic glutamate receptors (Hsieh et al, 2006;Um et al, 2013), a7 nicotinic acetylcholine receptors (Wang et al, 2000a,b;Snyder et al, 2005;Liu et al, 2012), paired immunoglobulin-like receptor B (Kim et al, 2013), cellular prion protein (Lauren et al, 2009;Um et al, 2013), and amylin receptors (Kimura et al, 2012).…”

“…Furthermore, exogenously added Ab can enter cells from the medium. Indeed, we recently found that Ab(1-42) inhibits the activity of the microtubule-dependent motor protein Eg5/kinesin-5 (also known as KIF11), which regulates a number of different important microtubule-dependent functions in neuronal and non-neuronal cells, including chromosome segregation, growth cone turning, and microtubule organization in axons and dendrites that may also indirectly impact membrane trafficking (Baas, 1998;Ferhat et al, 1998;Nadar et al, 2008;Borysov et al, 2011;Ari et al, 2014;Kahn et al, 2015).…”

Nebracetam Inhibited Hippocampus Neurons Injury Induced by Aβ25-35 in MRTF-A-CArG Manner via ERK1/2 Pathway

“…Various deranged mechanisms such as chronic oxidative stress [4], mitochondrial dysfunction [5,6], Aβ production [7], neurofibrillary tangles accumulation, hormone imbalance [8], inflammation, mitotic dysfunction [9], calcium mishandling [10], and genetic components [11] play a role in the disease process. Although the mechanisms are diverse, neuronal death, the inevitable event occurs resulting in AD.…”