Abstract
Alzheimer's Disease (AD) is characterized by neurofibrillary tangles, amyloid plaques and neurodegeneration. However, this pathology is preceded by increased soluble amyloid beta (Aβ) 1-42 oligomers that interfere with glutamatergic synaptic plasticity required for learning and memory, including N-methyl-D-aspartate receptor receptor (NMDAR)-dependent long-term potentiation (LTP). In particular, soluble Aβ(1-42) acutely inhibits LTP and chronically causes synapse loss. While many mechanisms are proposed for Aβ-induced synaptic dysfunction, we recently found that Aβ(1-42) inhibits the microtubule motor protein Eg5/Kinesin-5. Here we compared the impacts of Aβ(1-42) and monastrol, a small molecule Eg5 inhibitor, on LTP in hippocampal slices and synapse loss in neuronal cultures. Acute (20 min) treatment with monastrol, like Aβ, completely inhibited LTP at doses >100 nM. In addition, 1 nM Aβ(1-42) or 50 nM monastrol inhibited LTP ~ 50%, and when applied together, caused complete LTP inhibition. At concentrations that impaired LTP, neither Aβ(1-42) nor monastrol inhibited NMDAR synaptic responses until ~60 min, when only ~25% inhibition was seen for monastrol, indicating that NMDAR inhibition was not responsible for LTP inhibition by either agent when applied for only 20 min. Finally, 48 hour treatment with either 0.5-1.0 μM Aβ(1-42) or 1-5 μM monastrol reduced dendritic spine/synapse density in hippocampal cultures up to a maximum of ~40%, and when applied together at maximal concentrations, no additional spine loss resulted. Thus, monastrol can mimic, and in some cases occlude, the impacts of Aβ on LTP and synapse loss, suggesting that Aβ induces acute and chronic synaptic dysfunction in part through inhibiting Eg5.
- The American Society for Pharmacology and Experimental Therapeutics