Mots-C
Mitochondrial open reading frame of the 12S rRNA-c, MT-RNR1, Mitochondrial-derived peptide MOTS-c
Peripheral Administration of a Cell-Penetrating MOTS-c Analogue Enhances Memory and Attenuates Aβ<sub>1-42</sub>- or LPS-Induced Memory Impairment through Inhibiting Neuroinflammation.
Jiang. JinHong J; Chang. Xin X; Nie. YaoYan Y; Shen. YuXuan Y; Liang. XueYa X; Peng. YaLi Y; Chang. Min M
Key Findings
- MOTS‑c improves object and location memory in mice and reverses deficits caused by Aβ or LPS
- The memory benefit is blocked by an AMPK inhibitor, showing the effect works through AMPK activation
- Plain MOTS‑c doesn’t cross the blood‑brain barrier, but a cell‑penetrating version (MP) delivered intranasally or intravenously reaches the brain and restores memory
Practical Outcomes
- At this stage the findings are still pre‑clinical, so there’s no ready‑to‑use protocol for humans. However, the work suggests that if a brain‑penetrant form of MOTS‑c can be developed, it might become a novel tool for cognitive support. Biohackers should wait for safety and dosing data before trying any MOTS‑c‑based supplement.
Summary
Researchers found that a mitochondrial peptide called MOTS‑c can boost memory in mice and protect against memory loss caused by Alzheimer‑related proteins or inflammation, but the plain peptide doesn’t get into the brain on its own. By attaching it to a special cell‑penetrating carrier, it can reach the brain and still improve memory. The effect depends on activating the AMPK pathway and reducing brain inflammation.
Abstract
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<sub>1-42</sub> 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)<sub>5</sub>, 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.
Study Information
pubmed
2021
2021-04-16T00:00:00.000Z
10.1021/acschemneuro.0c00782
11
35