Mitochondrial Transfer Ameliorates Cognitive Deficits, Neuronal Loss, and Gliosis in Alzheimer’s Disease Mice

Article type: Research Article

Authors: Nitzan, Keren^{a; 1} | Benhamron, Sandrine^{a; 1} | Valitsky, Michael^a | Kesner, Eyal E.^{b; c} | Lichtenstein, Michal^b | Ben-Zvi, Ayal^d | Ella, Ezra^a | Segalstein, Yehudit^a | Saada, Ann^e | Lorberboum-Galski, Haya^{b; *} | Rosenmann, Hanna^{a; *}

Affiliations: [a] Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University medical center, Jerusalem, Israel | [b] Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada (IMRIC), Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel | [c] Department of Microbiology and Molecular Genetics, IMRIC, Faculty of Medicine, Hebrew University, Jerusalem, Israel | [d] Department of Developmental Biology and Cancer Research, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel | [e] Department of Genetic and Metabolic Diseases, Hadassah Hebrew University medical center, Jerusalem, Israel

Correspondence: [*] Correspondence to: Hanna Rosenmann, PhD, Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University medical center, Jerusalem, Israel. Tel.: +972 505172295; Fax: +972 3 7256022; E-mail: [email protected] and Haya Lorberboum-Galski, PhD, Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada (IMRIC), Faculty of Medicine, Hebrew University of Jerusalem, Israel. Tel.: +972 548820943; Fax: +972 26757529; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Pathogenesis of neurodegenerative diseases involves dysfunction of mitochondria, one of the most important cell organelles in the brain, with its most prominent roles in producing energy and regulating cellular metabolism. Here we investigated the effect of transferring active intact mitochondria as a potential therapy for Alzheimer’s disease (AD), in order to correct as many mitochondrial functions as possible, rather than a mono-drug related therapy. For this purpose, AD-mice (amyloid-β intracerebroventricularly injected) were treated intravenously (IV) with fresh human isolated mitochondria. One to two weeks later, a significantly better cognitive performance was noticed in the mitochondria treated AD-mice relative to vehicle treated AD-mice, approaching the performance of non-AD mice. We also detected a significant decrease in neuronal loss and reduced gliosis in the hippocampus of treated mice relative to untreated AD-mice. An amelioration of the mitochondrial dysfunction in brain was noticed by the increase of citrate-synthase and cytochrome c oxidase activities relative to untreated AD-mice, reaching activity levels of non-AD-mice. Increased mitochondrial activity was also detected in the liver of mitochondria treated mice. No treatment-related toxicity was noted. Thus, IV mitochondrial transfer may possibly offer a novel therapeutic approach for AD.

Keywords: Alzheimer’s disease, amyloid-ICV model, cognition, mitochondria, mitochondrial-transfer

DOI: 10.3233/JAD-190853

Journal: Journal of Alzheimer's Disease, vol. 72, no. 2, pp. 587-604, 2019