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

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-␤ 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.

Suan-Zao-Ren Decoction ameliorates synaptic plasticity through inhibition of the Aβ deposition and JAK2/STAT3 signaling pathway in AD model of APP/PS1 transgenic mice

“…SZRD increases the hippocampal neurons in CA3 and DG of APP/PS1 transgenic mice AD's pathological feature is the loss of in hippocampal neurons [34]. Hippocampal neurons are the biological basis of hippocampal-dependent learning and memory.…”

Blood–Brain Barrier and Neurovascular Unit In Vitro Models for Studying Mitochondria-Driven Molecular Mechanisms of Neurodegeneration

“…Restoration of mitophagy and inhibition of mitochondrial fission-promoting factor Drp1, whose interaction with Aβ results in defective mitophagy, might be beneficial for preventive neuronal death and cognitive deficits in Alzheimer’s type neurodegeneration [ 43 ]. However, some studies [ 44 ] have revealed that mitophagy is inhibited in neurons in Alzheimer’s disease, and stimulation of mitophagy might have a positive effect on the cognitive functions of experimental animals. Therefore, the exact role of aberrant mitophagy in neuronal damage in Alzheimer’s disease needs further clarification.…”

Extracellular Mitochondria Signals in CNS Disorders

“…In addition to therapies attacking amyloid-beta, targeting mitochondrial dysfunction may indirectly ameliorate AD pathology. Nitzan and colleagues have attempted mitochondrial transplantation to restore mitochondrial function in a mouse AD model produced by Aβ 1-42 intracerebroventricular infusion (Nitzan et al, 2019). Mitochondria isolated from HeLa cells were injected through the tail vein.…”

“…Moreover, mitochondrial functional parameters in the liver and brain were also restored. Collectively, mitochondrial transplantation through IV route can be a new therapeutic strategy for AD (Nitzan et al, 2019).…”