Peripheral Administration of a Cell-Penetrating MOTS-c Analogue Enhances Memory and Attenuates Aβ1–42- or LPS-Induced Memory Impairment through Inhibiting Neuroinflammation

MOTS-c is a 16-amino acid mitochondrial derivative peptide reported to be involved in regulating insulin and metabolic homeostasis via the AMP activated protein kinase (AMPK). AMPK agonist AICAR has been reported to improve cognition. Previous reports also pointed out that MOTS-c may be effective as a therapeutic option toward the prevention of the aging processes. Therefore, we investigated the roles of MOTS-c in the memory recognition process. The results showed that central MOTS-c not only enhanced object and location recognition memory formation and consolidation but also ameliorated the memory deficit induced by Aβ_1-42 or LPS. The memory-ameliorating effects of MOTS-c could be blocked by AMPK inhibitor dorsomorphin. Moreover, MOTS-c treatment significantly increased the phosphorylation of AMPK but not ERK, JNK, and p38 in the hippocampus. The underlying mechanism of MOTS-c neuroprotection may involve inhibiting the activation of astrocytes and microglia and production of proinflammatory cytokines. In addition, we found that peripheral administration of MOTS-c does not cross the blood-brain barrier (BBB) and plays an effect. In order to improve the brain intake of MOTS-c, we screen out (PRR)₅, a cell penetrating peptides, as a carrier for MOTS-c into the brain. Then in the NOR task, intranasal or intravenous MP (cell-penetrating MOTS-c analogue) showed good memory performance on memory formation, memory consolidation, and memory impairment. Near-infrared fluorescent experiments showed the real-time biodistribution in brain after intranasal or intravenous infusion of MP. These results suggested that MOTS-c might be a new potential target for treatment of cognitive decline in AD.