Real-time imaging of mitochondrial redox reveals increased mitochondrial oxidative stress associated with amyloid β aggregates in vivo in a mouse model of Alzheimer’s disease

Author:

Calvo-Rodriguez MariaORCID,Kharitonova Elizabeth K.,Snyder Austin C.,Hou Steven S.,Sanchez-Mico Maria Virtudes,Das Sudeshna,Fan Zhanyun,Shirani Hamid,Nilsson K. Peter R.,Serrano-Pozo Alberto,Bacskai Brian J.ORCID

Abstract

AbstractBackgroundReactive oxidative stress is a critical player in the amyloid beta (Aβ) toxicity that contributes to neurodegeneration in Alzheimer’s disease (AD). Mitochondrial damage, observed in AD, is one of the main sources of reactive oxygen species. Although Aβ causes neuronal mitochondria-associated reactive oxidative stress in vitro, this has never been directly observed in the in vivo living brain. Here, we tested whether Aβ plaques and soluble oligomers induce mitochondrial oxidative stress in surrounding neurons in vivo, and whether the neurotoxic effect can be abrogated using mitochondrial-targeted antioxidants.MethodsWe expressed a genetically encoded fluorescent ratiometric mitochondria-targeted reporter of oxidative stress in mouse models of the disease, and performed intravital multiphoton microscopy of neuronal mitochondria and Aβ plaques.ResultsFor the first time, we demonstrated by direct observation exacerbated mitochondrial oxidative stress in neurons after both Aβ plaque deposition and direct application of soluble oligomeric Aβ onto the brain, and determined the most likely pathological sequence of events leading to oxidative stress in vivo. Oxidative stress could be inhibited by both blocking calcium influx into mitochondria and treating with the mitochondria-targeted antioxidant SS31.ConclusionsConsidering these results, mitochondria-targeted compounds hold promise as neuroprotective drugs for the prevention and/or treatment of AD.

Publisher

Cold Spring Harbor Laboratory

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