Peripheral administration of a cell-penetrating MOTS-c analogue enhances memory and attenuates Aβ1-42 or LPS induced memory impairment through inhibiting neuroinflammation

Background: MOTS-c is a 16-amino acid mitochondrial derivative peptide reported to be involved in regulating insulin resistance and obesity, osteoporosis and inflammatory responses. Accumulating evidences suggest that inhibiting neuroinflammation is a potential target in therapeutic or preventive strategies for Alzheimer’s disease (AD). Due to the widespread distribution of MOTS in the CNS and its role in metabolism and immune system, previous reports also pointed out that MOTS-c may be effective as a therapeutic option toward the prevention of the aging processes. Therefore, it is important to understand the roles of MOTS-c in neuroinflammation. Methods: The mouse memory function was evaluated using novel object recognition (NOR) and object location recognition (OLR) tasks. Brain hippocampus tissue samples were analyzed by quantitative PCR, western blotting, ELISA and immunostaining. Near-infrared fluorescent and confocal microscopy experiments were used to detect the brain uptake and distribution of intranasal or intravenous MOTS-c or MP (MOTS-c conjugated with cell penetrating peptides). Peptides drugs were synthesized by a standard Fmoc-based solid-phase synthetic method. Results: Central MOTS-c enhances object and location recognition memory formation and consolidation, and ameliorates the memory deficit induced by Aβ1-42 or LPS in NOR and OLR tasks, whereas dorsomorphin (AMPK inhibitor, i.p.) significantly blocked the memory-ameliorating effects of MOTS-c. Western blotting experiments showed that MOTS-c provided neuroprotection against LPS or Aβ1-42-induced neuroinflammation, which was related with phosphorylation of AMPK, but not MAPK including ERK, JNK and p38. The underlying mechanism of MOTS-c neuroprotection may be involved of inhibiting the activation of astrocytes and microglia and production of proinflammatory cytokines including TNF-α, IL-6, IL-1β, COX-2 and iNOS. 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 NOR task, intranasal or intravenous MP, but not MOTS-c, showed good memory performance on memory formation, memory consolidation and memory impairment. Finally, compared with control and Rho-MOTS-c groups, significant fluorescence signals of Rho-MP were detected in the brain by NIR fluorescence imaging. Conclusion: MOTS-c might be a new potential target for treatment of cognitive decline in AD and this way of administration MP will be the potential strategy for non-invasive therapeutic intervention.