Objective To explore the neuroprotective effect of APP5-mer Peptide Memantine （RERMS-MEM） on glutamate-induced injury of SY5Y cells. Methods SY5Y cells were cultured aseptically， and the injury model was established with high concentration of L-glutamic acid（ 10 mM）. RERMS-MEM was self-designed and synthesized. After screening the effective concentration of drugs by MTT method， SY5Y cells were divided into control group， L-glu injury group， L+RM group（ L-glu+RERMS-MEM） and L+M group（ L-glu+MEM）. MTT assay was used to detect the survival rate of cells， LDH kit was used to detect the leakage rate of LDH in supernatant， Western blot was used to detect the expression of nerve growth factor （NGF） and BDNF protein， real-time fluorescence quantitative PCR was used to detect the expression of NGF and BDNF mRNA， DCFH-DA kit was used to detect the expression of reactive oxygen species（ ROS） in each group. Results MTT assay was used to detect the effect of RERMS-MEM on the survival rate of SY5Y cells damaged by L-glu. Compared with control group［ cell survival rate was（ 100.00±5.01） %］， the cell survival rate decreased to（ 74.89±4.94） % in L-glu group， the difference was statistically significant（ P ＜ 0.05）. Compared with L-glu group， the survival rate of cells treated with RERMS-MEM at 1， 5， 10 and 20 μM was （86.40±14.81）%，（ 90.24±5.87） %，（ 90.47±8.10） % and（ 91.84±11.60） %， respectively， showing a dosedependent increase in cell survival rate with RERMS-MEM， and the difference was statistically significant at 5，10， and 20μM intervention（ all P＜0.05）. Compared with L-glu group， the cell survival rate of L+M group at low concentration（ 1， 5， 10 μ m） was improved， but the difference was not statistically significant（ all P＞ 0.05）. After 20 μM intervention， the cell survival rate was significantly reduced to（ 61.37±10.32）%， and the difference was statistically significant（ P ＜ 0.05）. Finally， 5μM was selected as the intervention dose of RERMS-MEM and MEM. The results of Muse cell analyzer showed that the number of living cells in the L-glu group was significantly lower than that in the control group（ P ＜ 0.01）. Compared with the L-glu group， the number of living cells in the L+RM group was significantly increased after RERMS-MEM intervention， and the difference was statistically significant（ P ＜ 0.01）. After MEM intervention in L+M group， the number of living cells increased less than that in L+RM group， and the difference was not statistically significant（ P ＞ 0.05）. LDH test results showed that compared with the control group， the LDH leakage rate of the L-glu group was significantly increased， and the difference was statistically significant（ P＜0.01）. Compared with the L-glu group， the LDH leakage rate of the L+RM group was significantly reduced， and the difference was statistically significant（ P＜ 0.01）. The LDH leakage rate of the L+M group was also reduced， but the difference was not statistically significant（ P ＞ 0.05）. The results of Western Blot and RT-qPCR showed that compared with the control group， the relative expression of NGF protein and mRNA in the L-glu group was significantly decreased， and the difference was statistically significant（ all P ＜ 0.05）. Compared with the L-glu group， the expression levels of L+RM group and L+M group were significantly increased， and the differences were statistically significant（all P ＜ 0.05）. And the L+RM group showed higher NGF protein and mRNA expression levels compared to the L+M group. BDNF detection results indicated a statistically significant difference between the L+M group and the L-glu group（P ＜ 0.05）. The relative mRNA expression level was not significantly increased， but the difference between the L+M group and the L-glu group was statistically significant（ P ＜ 0.05）. Compared with the control group， ROS expression levels in the L-glu group were significantly elevated by two detection methods， and the difference was statistically significant（ P＜0.05）. Compared with the L-glu group， ROS expression in both the L+RM group and the L+M group was reduced， and the difference was statistically significant（ both P＜0.05）， and the reduction was more pronounced in the L+RM group. Compared with the control group， the total cell apoptosis rate in the L-glu group was increased， and the difference was statistically significant（ P ＜ 0.01）. Compared with the L-glu group， the total cell apoptosis rates in both the L+RM group and the L+M group were reduced， and the difference was statistically significant（ both P＜0.01）. Conclusions APP5-mer Peptide memantine has better neuroprotective effect and lower cytotoxicity in vitro than memantine. The neuroprotective effect of RERMS-MEM may be realized by inhibiting apoptosis， oxidative stress injury and increasing the expression of neurotrophic factors.