Amyloid Beta and Tau Proteins as Therapeutic Targets for Alzheimer’s Disease Treatment: Rethinking the Current Strategy
The role of GSK3β and Fyn during AD-related neurodegeneration and memory formation, along with NMDA receptor, makes them important therapeutic targets (red square). Impairment of hippocampal LTP by Aβ is through direct interaction with NMDA receptor. 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 GSK3β that determines whether NMDA receptor activation induces LTD or inhibits LTD. Aβ leads to decreased mitochondria and oxidative injury that promotes the release of cytochrome C (Cyt C) that may activate caspase-9 and caspase-3, which can cleave Akt, resulting in GSK3β activation. GSK3β under the control of Akt and PP1, is a critical determinant of the direction of NMDA receptor-dependent plasticity. The active GSK3β isoforms critically contribute to neurodegeneration by hyperphosphorylation of tau which deregulates Fyn activity and consequently affects NMDA receptor response.