In vivo positron emission tomography imaging of mitochondrial abnormalities in a mouse model of tauopathy

Damaged mitochondria may be one of the earliest manifestations of Alzheimer`s disease (AD). Since oxidative phosphorylation is a primary source of neuronal energy, unlike glycolysis-dependent energy production in inflamed glia, mitochondrial respiration could provide a selective biomarker of neuronal deterioration in AD. Here we used a recently developed positron emission tomography (PET) probe targeting mitochondrial complex I (MC-I), 18F-BCPP-EF, to non-invasively visualize mitochondrial abnormalities in the brains of tau transgenic mice (rTg4510 TauTg). Tauopathy and neuroinflammation were visualized by PET using a tau probe 11C-PBB3 and a TSPO probe, 18F-FEBMP, respectively. A marked reduction in 18F-BCPP-EF uptake was observed in hippocampal and forebrain regions of TauTg mice, colocalizing with regions of tauopathy, neuronal damage and neuroinflammation. MC-I signals were highly correlated with atrophy assayed by MRI, but negatively associated with inflammatory signals measured by TSPO-PET, indicating that neuronal metabolic signals measured by MC-I PET were robust to inflammatory interference. MC-I may be a useful imaging biomarker to detect neuronal damage and metabolic changes with minimal interference from concomitant glial hypermetabolism.Ministry of Education (MOE)Submitted/Accepted versionThis work was supported by grant-in aid for Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS; 15653129 to TS and MH and 19189478 to MH); Research and Development Grants for Dementia (16768966 to MH); grant-in-Aid for Science Research on Innovation Area (“Brain Protein Aging” 26117001 to NS) and Science Research (C) (15K09979 to BJ) from the Ministry of Education, Culture, Sports, Science and Technology, Japan; the strategic Research Program for Brain Science from Japan Agency for Medical Research and Development, AMED (JP18dm0107094 to TS and JP18dm0107062 to NS, and 18dm0207007h0005 and 17dm0107066h to IA); Nanyang Assistant Professorship from Nanyang Technological University Singapore (to AMB); Alzheimer’s Association (AARG-18-566427 to AMB); and Singapore Ministry of Education (2018-T1-001-041 to AMB)