Inhibition of the Motor Protein Eg5/Kinesin 5 in Amyloid b Mediated Impairment of Hippocampal Long Term Potentiation and Dendritic Spine Loss
Alzheimer's disease (AD) is characterized by neurofibrillary tangles, amyloid plaques, and neurodegeneration. However, this pathology is preceded by increased soluble amyloid beta (Ab) 1 42 oligomers that interfere with the glutamatergic synaptic plasticity required for learning and memory, including N methyl d aspartate receptor (NMDAR) dependent long term potentiation (LTP) In particular, soluble Ab(1 42) acutely inhibits LTP and chronically causes synapse loss. Many mechanisms have been proposed for Ab induced synaptic dysfunction, but we recently found that Ab(1 42) inhibits the microtubule motor protein Eg5/kinesin 5. Here we compared the impacts of Ab(1 42) and monastrol, a small molecule Eg5 inhibitor, on LTP in hippocampal slices and synapse loss in neuronal cultures. Acute (20 minute) treatment with monastrol, like Ab, completely inhibited LTP at doses >100 nM. In addition, 1 nM Ab(1 42) or 50 nM monastrol inhibited LTP #x223c;50% and when applied together caused complete LTP inhibition. At concentrations that impaired LTP, neither Ab(1 42) nor monastrol inhibited NMDAR synaptic responses until #x223c;60 minutes, when only #x223c;25% inhibition was seen for monastrol, indicating that NMDAR inhibition was not responsible for LTP inhibition by either agent when applied for only 20 minutes. Finally, 48 hours of treatment with either 0.5 1.0 mM Ab(1 42) or 1 5 mM monastrol reduced the dendritic spine/synapse density in hippocampal cultures up to a maximum of #x223c;40% and when applied together at maximal concentrations, no additional spine loss resulted. Thus, monastrol can mimic and in some cases occlude the impact of Ab on LTP and synapse loss, suggesting that Ab induces acute and chronic synaptic dysfunction in part through inhibiting Eg5.
Molecular Pharmacology