Memory formation in old age requires GSK-3β

Abstract Glycogen synthase kinase 3β (GSK-3β) is a therapeutic target for various age-related neurodegenerative diseases. It is linked to the two main pathological features of Alzheimer’s disease (AD), tau and amyloid β (Aβ); GSK-3β is a major candidate to pathologically hyperphosphorylate tau and modulate Aβ production. However, inhibition of GSK-3β in clinical studies in humans has been found to not significantly improve cognitive function of AD patients, prompting us to study the physiological role of GSK-3β in old mice. Using a contextual fear-conditioning paradigm, we now report that old gsk-3β+/− mice are deficient in both short-term and long-term memory formation, suggesting that GSK-3β is required for memory formation at old age. Biochemical and immunohistochemical analyses showed that the number of synapses does not differ between gsk-3β+/− and age-matched wild-type (wt) littermate mice. Based on these observations, we propose that, GSK-3β may contribute to help maintain brain function during aging. Our results may explain the poor efficacy of GSK-3β inhibitors in preserving memory capacity in AD patients.