A novel neuroprotection target with distinct regulation in stroke and Alzheimer’s disease

Abstract

Stroke and Alzheimer’s disease (AD) share a common mechanism of neuronal death known as excitotoxicity. Therapeutic approaches blocking excitotoxic responses, with agents, such as the NMDA receptor antagonist memantine, inhibitors of the protease calpain or GSK3 have been tested in poststroke and AD treatments. Novel therapies for neuroprotection are based on the use of cell-penetrating peptides (CPPs) targeting molecules and signaling pathways involved in neurodegeneration. The study of the molecular mechanisms that regulate the levels of the prosurvival protein Kidins220/ARMS in acute versus chronic AD-related neurodegeneration has established a clear parallelism with those controlling tau proteostasis that involve changes in GSK3 phosphorylation and calpain processing. The development of a neuroprotective CPP derived from this molecule, effective against acute excitotoxicity provide new evidence to support the use of GSK3 inhibitors in combination with specific CPPs as a novel strategy to reduce neuronal damage in AD.