Aging‐Induced Episodic‐Like Memory Impairment Could be Alleviated by Melatonin Treatment via Preserving Blood–Brain Barrier Integrity and Upregulating CRTC1

ABSTRACT Background Aging is accompanied by impairments in stimulus recognition, and decreased melatonin levels have been shown in aged mice and humans. These age‐related changes are associated with an increased risk of neurological diseases. In the present study, our aim is to investigate whether melatonin supplementation could ameliorate age‐related cognitive decline in aged mice. Methods Mice were treated with melatonin or saline. The novel object recognition (NOR) task was used to provide a simultaneous assessment of object and object location memory, which is a component of episodic‐like memory. Blood–brain barrier (BBB) leakage was assessed using an Immunoglobulin G (IgG) leakage assay. Immunofluorescence and Western blot analyses were employed to investigate changes in protein levels. Results We demonstrate that aging impairs memory in the NOR task, with concomitant decreases in the levels of synaptophysin (SYP), CREB‐regulated transcription coactivator 1 (CRTC1), and phosphorylated AMP‐activated protein kinase (p‐AMPK) levels within the prefrontal cortex (PFC) and hippocampus. Moreover, alongside compromised BBB integrity, aging results in the degradation of occludin in both the PFC and hippocampus. Our findings demonstrate that aging impairs memory performance in the NOR task, accompanied by reductions in SYP, CRTC1, and p‐AMPK levels within the PFC and hippocampus. Furthermore, alongside compromised BBB integrity, aging results in the degradation of occludin in both the PFC and hippocampus. More importantly, PDZ and LIM domain 5 (Pldim5) was upregulated in melatonin‐treated mice, and aging‐related memory impairment in the NOR task was significantly reduced in Pdlim5 −/− mice. Notably, 1 week of melatonin (10 mg/kg) treatment significantly improved memory, along with enhanced BBB integrity, Pdlim5 downregulation, and CRTC1 and p‐AMPK upregulation. Conclusions Taken together, our findings suggest that melatonin ameliorates aging‐related memory decline in the NOR task by downregulating Pdlim5, maintaining BBB integrity, and upregulating CRTC1 and p‐AMPK in aged mice.