The Beneficial Effect of Mitochondrial Transfer Therapy in 5XFAD Mice via Liver–Serum–Brain Response

Sahar Sweetat, Keren Nitzan, Nir Suissa, Yael Haimovich, Michal Lichtenstein, Samar Zabit, Sandrine Benhamron, Karameh Akarieh, Kumudesh Mishra, Dinorah Barasch, Ann Saada, Tamar Ziv, Or Kakhlon, Haya Lorberboum-Galski*, Hanna Rosenmann*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

We recently reported the benefit of the IV transferring of active exogenous mitochondria in a short-term pharmacological AD (Alzheimer’s disease) model. We have now explored the efficacy of mitochondrial transfer in 5XFAD transgenic mice, aiming to explore the underlying mechanism by which the IV-injected mitochondria affect the diseased brain. Mitochondrial transfer in 5XFAD ameliorated cognitive impairment, amyloid burden, and mitochondrial dysfunction. Exogenously injected mitochondria were detected in the liver but not in the brain. We detected alterations in brain proteome, implicating synapse-related processes, ubiquitination/proteasome-related processes, phagocytosis, and mitochondria-related factors, which may lead to the amelioration of disease. These changes were accompanied by proteome/metabolome alterations in the liver, including pathways of glucose, glutathione, amino acids, biogenic amines, and sphingolipids. Altered liver metabolites were also detected in the serum of the treated mice, particularly metabolites that are known to affect neurodegenerative processes, such as carnosine, putrescine, C24:1-OH sphingomyelin, and amino acids, which serve as neurotransmitters or their precursors. Our results suggest that the beneficial effect of mitochondrial transfer in the 5XFAD mice is mediated by metabolic signaling from the liver via the serum to the brain, where it induces protective effects. The high efficacy of the mitochondrial transfer may offer a novel AD therapy.

Original languageAmerican English
Article number1006
JournalCells
Volume12
Issue number7
DOIs
StatePublished - 24 Mar 2023

Bibliographical note

Publisher Copyright:
© 2023 by the authors.

Keywords

  • 5XFAD
  • Alzheimer’s disease
  • amyloid
  • cognition
  • mitochondria
  • mitochondrial transfer

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