Damaged mitochondria may be one of the earliest manifestations of Alzheimer's disease (AD), with mitochondrial bioenergetic dysfunction observed long before symptomatic onset both clinically and in mouse models of the disease. The aim of this study was to evaluate mitochondrial abnormalities in the brains of living tau transgenic (tauTg, rTg4510) mice using a novel PET probe targeting mitochondrial complex I (MC-I), which mediates the first and rate-limiting step in oxidative phosphorylation.
MC-I, tau deposition and inflammatory signals were assessed in the brains of living non-Tg and tauTg mice at 2 and 7 months of age by PET using 18F-BCPP-EF, 11C-PBB3, and 18F-FEBMP, respectively. Brain atrophy was also evaluated by volumetric MRI, and learning and memory impairments were assessed in the Y-maze. In vivo signals were confirmed by autoradiography and immunohistochemistry in brain sections from scanned mice.
A progressive, age-dependent reduction in 18F-BCPP-EF uptake was observed in hippocampal and forebrain regions of tauTg mice, coinciding with the development of tau lesions detected by 11C-PBB3 PET. A strong association was observed between MC-I signals detected by PET, hippocampal volume assessed by MRI, and learning and memory performance in the Y-maze task. In vivo findings were confirmed by 18F-BCPP-EF autoradiography and immunohistochemistry for AT-8 (tau phosphorylation), GFAP (astrocytes), IBA-1 (microglia), NeuN (neurons).
MC-I PET may provide a useful non-invasive imaging biomarker for the real-time identification of early-stage mitochondrial abnormalities associated with tau-induced neurodegenerative cascades.
© 2017 Published by Elsevier Inc.