Effects Of Proteasome Inhibition On The Spatial Cognition Of Mice And The Underlying Mechanisms

Ubiquitin-proteasome system (UPS), which is one of the most important system of intracellular protein degradation. UPS mainly contains ubiquitin activating enzyme El, ubiquitin conjugating enzyme E2, ubiquitin ligase E3, deubiquitinating enzymes and proteasome and so on. It plays critical roles in many physiological processes such as synaptic plasticity, axonal growth and dendritic spine formation. UPS impairment has been reported involved in severals nervous system disease, such as Parkinson's disease and Alzheimer's disease. In our research, we studied the effect of proteasome inhibition on the cognitive ability of mice and explored the mechanisms in N2a cells and Mus musculus mice. First, we treated N2a neuroma cell line with 0.5μM,1.0μM and 2.0μM MG132 (a specific inhibitor of proteasome) for 24 h, then detected the change of cellular morphology, the activities of cAMP-response element binding protein (CREB), a key transcriptional factor involved in the formation of synapse and synaptic plasticity, and content of postsynaptic density-95 (PSD-95). We also investigated the effect of proteasome inhibition on the phosphorylated tau and the biological of tau of binding to the microtubules by Western blotting. Results:(1) In N2a cells, MG132 treatment resulted in decrease of the length and number of neurites. (2) MG132 treatment decreased the contents of CREB, p-CREB and PSD-95. (3) MG132 treatment increased the level of total tau and phosphorylated tau at Ser396, Ser262, Serl95/198/199/202, Thr231 and Thr205 sites, and decreased its binding ability to microtubule. Second, we used MG132 stereotaxic injecting in lateral ventricle of mice for 24 h and then detected the alteration of spatial cognitive ability of mice by water maze, we also observed the change of neuritis, CREB activity, PSD-95 content and phosphorylation of tau protein. Results:(1) MG132 treatment impaired spatial cognition of mice. (2) MG132 treatment reduced the length and the number of neuritis, the activity of CREB and the content of PSD-95. (3) MG132 treatment increased tau-Ser396, Ser262, Ser195/198/199/202, Thr231 and Thr205 sites phosphoryation. In conclusion, our results manifested that proteasome inhibition impaired spatial cognition of mice. The atrophy of neuritis, decrease of CREB activity and reduction of PSD-95 content, and abnormal phosphorylation of tau protein might involve in the mechanisms.