Glycogen Synthase Kinase 3: A Point of Integration in Alzheimer's Disease and a Therapeutic Target?
Figure 1
Cocktail drugs could balance the activity of GSK3 during AD. The role of PP1 and Akt in GSK3 activation, in combination with NMDA receptor, makes them important therapeutic targets. Calcium (Ca2+) enters via NMDA receptors, and this leads to activation of protein phosphatase 1 (PP1), a key enzyme in synaptically induced LTD. PP1 can dephosphorylate GSK3 that determines whether NMDA receptor activation induces LTD or inhibits LTD. PP1 can dephosphorylate Akt, resulting in GSK3 activation. GSK3, under the control of Akt and PP1, is a critical determinant of the direction of NMDA receptor-dependent plasticity. The active GSK3 isoforms contribute to phosphorylation of tau protein which is essential in order for the protein to function as a negative feedback mechanism to prevent NMDA-receptor overexcitation and synaptic failure.
