Activation of autophagy protects D - galac - tose induced aging rat brain through mTOR / Akt / CREB pathway

Introduction: Autophagy is catabolic process involved in continuous removal of toxic protein aggregates and cellular organelles to maintain the homeostasis and functional integrity of cells. The mechanistic understanding of autophagy-mediated neuroprotection during aging remains exclusive. Here, we investigated the potential role of rapamycin-induced activation of autophagy and mTOR/Akt/CREB pathway(s) in the neuroprotection of D-galactose-induced aging brain of rats. Material and Methods: Adult male wistar rats were treated with D-galactose (500 mg/kg b.w., s.c., daily for 45 days) to establish the model of aging. Further, the effect of autophagy inducerrapamycin (0.5 mg/kg b.w., oral, daily for 30 days) has been studied on D-galactose-induced oxidative stress, synaptic/neurotransmission/cognitive dysfunction. Results: The administration of D-galactose impaired redox balance, induced synaptic/neurotransmission/ cognitive dysfunctions and suppressed pro-survival signaling in adult rats. Rapamycin administration caused a significant reduction of mTOR phosphorylation at Ser2481 and a significant increase in autophagy markers such as microtubule-associated protein-1 light chain-3 (LC3), Beclin-1, sequestosome-1/p62, unc-51-like kinase 1 (ULK1). In addition, rapamycin-induced activation of autophagy further activated p-Akt (Ser473), p-CREB (Ser183) expression in Dgalactose treated rats. The activated autophagy markedly reversed D-galactose-induced impaired redox homeostasis. The activated autophagy also provided significant neuroprotection against Dgalactose-induced synaptic dysfunction by increasing the expression of synapsin-I, synaptophysin and PSD95, neurotransmission dysfunction by increasing the levels of CHRM2, DAD2 receptor, NMDA receptor and AMPA receptor, and ultimately improved cognitive ability in rats. Conclusion: Our study demonstrate that autophagy can be an integrated part of pro-survival (mTOR/Akt/ CREB) signaling that restores the oxidative defense mechanism(s) and maintains the integrity of synapse and neurotransmission in Dgalactose induced rat model of aging.