Fig. 5.

Schematic diagram of the mechanisms involved in CP2-mediated neuroprotection. Mechanisms of CP2-dependent restoration of pTau-mediated synaptic dysfunction. Under physiological conditions, tau transports Fyn to the dendritic spines where Fyn phosphorylates the NR2B subunit of NMDARs at Y-1472 leading to the stabilization of the NMDAR:PSD95 complex. Increased tau phosphorylation leads to the destabilization of the NMDAR:PSD95 and AMPAR:PSD95 complexes with increased AMPAR endocytosis resulting in reduced synaptic strength and LTP. Partial inhibition of MCI with CP2 increases AMP/ATP ratio that directly activates AMPK with concomitant effect on the activity of PP2Ac, CDK5, and GSK3β resulting in a significant reduction in pTau levels. Reduction in pTau and Fyn results in the stabilization of the NMDAR and AMPAR complexes and improved LTP leading to enhanced cognitive function in 3xTg-AD mice.