Beneficial effects of mitochondrial transfer therapy in Alzheimer’s disease mouse models

Background: The pathogenesis of neurodegenerative diseases involves dysfunction of the mitochondria, one of the most important cell organelles in the brain, with its most prominent roles of producing energy and regulating cellular metabolism. Aiming to affect as many of the mitochondrial complex functions, rather than a mono-drug related therapy, here we investigated the effect of transferring normal intact mitochondria organelles in Alzheimer`s disease (AD)-mouse models. Methods: I. Amyloid-beta (Ab) ICV injected AD-model mice were IV treated with fresh mitochondria isolated from human cells. One to two weeks later, cognitive tests were performed followed by histological analysis (neuronal count and glial burden), and biochemical analysis (mitochondrial enzymatic activities). II. 5XFAD-Tg mice were IV treated (1/ 2wks at 5-6 month of age). Cognitive tests were performed, followed by histological and biochemical analysis. Results: Amelioration of cognitive deficits was noticed in the mitochondria treated Ab-ICV-AD-mice relative to vehicle treated mice, with a decrease in neuronal loss and reduced gliosis in the hippocampus. Amelioration of the brain mitochondrial dysfunction also was noticed: increased of citrate- synthase and cytochrome c oxidase activities relative to untreated AD-mice. The IV transferred mitochondria were detected in the liver, accompanied with increased liver mitochondrial activity, thereby suggesting a liver mediated effect of the transferred mitochondria on the brain. No treatment-related toxicity was noted. A beneficial effect of mitochondrial transfer was also detected in Tg-5XFAD mice. Conclusions: Thus, IV mitochondrial transfer may offer a novel therapeutic approach for AD.