Tau Protein Preferentially Associates With Synaptic Mitochondria in a Mouse Model of Tauopathy

Abstract BackgroundA consequence of an aging society is a continual and dramatic increase in the number of patients suffering from tauopathies, including Alzheimer’s disease (AD) and certain frontotemporal dementias. Accumulation of intracellular inclusions of abnormal fibrillar forms and hyperphosphorylated forms of microtubule-associated protein tau are hallmarks of AD and other tauopathies. Although tau pathology is associated with neuronal dysfunction the mechanism responsible remains obscure. In vitro, pathologically elevated expression of tau alters mitochondrial distribution by impairing cellular trafficking and thus may represent an important mediator of mitochondrial abnormalities contributing to neuronal dysfunction. We used the transgenic htau mouse model of tauopathy to investigate in vivo alterations in brain mitochondria in the presence of pathological forms of human tau.MethodsIn this study, we investigated alterations in bioenergetics and profiled the proteome of brain mitochondria from wild-type (WT) and htau mice at ages prior to and coinciding with pathologic tau deposition in htau mice. In addition, we characterized the expression of total and hyperphosphorylated forms of tau associated with synaptic mitochondria by biochemical fractionation and immunoblotting.ResultsSignificant tau pathology-dependent alterations in synaptic mitochondrial bioenergetics were observed at 8 mo nths, but not 5 months, of agein htau mice; however, non-synaptic mitochondrial function remained unaltered. Further, compared to control mice, proteins involved in microtubule-based movement were differentially expressed in htau mice at 8 months of age. In addition, significant accumulation of tau and its hyperphosphorylated forms was observed in synaptic mitochondria isolated from 8-month-old htau mice.ConclusionThese data suggest that tau preferentially associates with synaptic mitochondria as compared to non-synaptic mitochondria, and accumulation of pathologic forms of tau coincides with synaptic mitochondrial bioenergetic changes reminiscent of an aged synaptic mitochondrial phenotype reported in aging WT mice. Furthermore, the mitochondrially associated tau is soluble in carbonate buffer and more accessible to protease action suggesting it is not integrated into mitochochondrial membranes, but may rather be the result of protein-protein interactions.