Brain dysfunction,especially cognitive impairment,is one of the main complications in Alzheimer’s disease (AD),which threatens the health of 46.8 million people worldwide.At present,the pathogenesis of cognitive dysfunction is only partially understood,and effective therapies for memory loss in AD remain elusive.Tetramethylpyrazine (TMP) is one of the major bioactive compounds purified from Chuanxiong,a Chinese herb used for the treatment of neurovascular and cardiovascular diseases.The neuroprotective properties of TMP are evident in some neurodegenerative diseases,including Parkinson’s disease.However,whether TMP plays a neuroprotective role in AD is still unknown.Here,we report that 2-week treatment with TMP rescued both shortterm and long-term fear memory impairment induced by intracerebroventricular injection of streptozotocin in a well-known AD rat model.Administration of TMP also restored spatial leing and memory retention abilities in streptozotocin-injected rats.Furthermore,TMP inhibited the activity of GSK-3β,an important kinase that mediates hippocampal synaptic and memory disorders in diabetes mellitus.Finally,we found that TMP treatment restored the function of cholinergic neurons.Our data suggest that dietary uptake of TMP can provide protection against memory loss in AD,and the inhibition of GSK-3β may play an important role in this protective effect.