Mitochondrial complex I as a diagnostic and therapeutic target in a mouse model of tauopathy

Abstract

Dysfunction of the energy producing organelle of the cell, mitochondria, plays a pivotal role in Alzheimers disease (AD). We have recently used a novel positron emission tomographic (PET) imaging tracer targeting mitochondrial complex I (MC-I) to visualize mitochondrial abnormalities in the brains of living tau transgenic (TauTg) mice. MC-I mediates the first and limiting step in oxidative phosphorylation, the primary source of neuronal energy production. Here we used MC-I-PET to test if inhibition of mutant tau expression through transgene suppression with doxycycline could reverse mitochondrial defects in a mouse model of tauopathy and evaluate the efficacy of a MC-I-targeted candidate therapeutic, Mdivi-1. We found that late-stage suppression of mutant tau did not rescue mitochondrial deficits measured in vivo by MC-I-PET, despite reduced burden of tauopathy and neuroinflammation. These findings demonstrate that mitochondrial dysfunction may continue even if tauopathy is halted, particularly if initiated at late-stage disease. Further, we demonstrate the potential application of MC-I-PET for monitoring therapeutic efficacy, surprisingly finding detrimental effects of the mitochondrial-targeted candidate therapeutic, Mdivi-1, in TauTg mice. These findings directly contrast with the beneficial effects of Mdivi-1 observed in other models of neurodegeneration. Together, our findings highlight the need for clinical endpoints measuring mitochondrial damage in addition to markers of tauopathy in the assessment of disease prognosis and efficacy of candidate therapeutics and demonstrates the potential application of MC-I-PET to meet this need.