Ceftriaxone improves impairments in synaptic plasticity and cognitive behavior in APP/PS1 mouse model of Alzheimer's disease by inhibiting extrasynaptic NMDAR‐STEP61 signaling

Abstract Abnormal activation of the extrasynaptic N‐methyl‐ d ‐aspartate receptor (NMDAR) contributes to the pathogenesis of Alzheimer's disease (AD). Ceftriaxone (Cef) can improve cognitive impairment by upregulating glutamate transporter‐1 and promoting the glutamate–glutamine cycle in an AD mouse model. This study aimed to investigate the effects of Cef on synaptic plasticity and cognitive‐behavioral impairment and to unravel the associated underlying mechanisms. We used an APPswe/PS1dE9 (APP/PS1) mouse model of AD in this study. Extrasynaptic components from hippocampal tissue homogenates were isolated using density gradient centrifugation. Western blot was performed to evaluate the expressions of extrasynaptic NMDAR and its downstream elements. Intracerebroventricular injections of adeno‐associated virus (AAV)‐striatal enriched tyrosine phosphatase 61 (STEP 61 ) and AAV‐STEP 61 ‐shRNA were used to modulate the expressions of STEP 61 and extrasynaptic NMDAR. Long‐term potentiation (LTP) and Morris water maze (MWM) tests were performed to evaluate the synaptic plasticity and cognitive function. The results showed that the expressions of GluN2B and GluN2B Tyr1472 in the extrasynaptic fraction were upregulated in AD mice. Cef treatment effectively prevented the upregulation of GluN2B and GluN2B Tyr1472 expressions. It also prevented changes in the downstream signals of extrasynaptic NMDAR, including increased expressions of m‐calpain and phosphorylated p38 MAPK in AD mice. Furthermore, STEP 61 upregulation enhanced, whereas STEP 61 downregulation reduced the Cef‐induced inhibition of the expressions of GluN2B, GluN2B Tyr1472 , and p38 MAPK in the AD mice. Similarly, STEP 61 modulation affected Cef‐induced improvements in induction of LTP and performance in MWM tests. In conclusion, Cef improved synaptic plasticity and cognitive behavioral impairment in APP/PS1 AD mice by inhibiting the overactivation of extrasynaptic NMDAR and STEP 61 cleavage due to extrasynaptic NMDAR activation. image