Targeting mTOR restores tau-induced metabolic, mitochondrial, and cognitive deficits in a tauopathy mouse model

AimHyperphosphorylated tau is a hallmark of Alzheimers disease (AD). However, whether mammalian target of rapamycin (mTOR) directly regulates tau phosphorylation at Ser214, Ser356, and Thr231 and how such regulation affects mitochondrial function remain unclear. In this study, we aimed to determine whether mTOR-mediated tau phosphorylation disrupts mitochondrial and metabolic profiles and cognitive function and whether these effects can be reversed by the mTOR inhibitor rapamycin. MethodsTau3E-overexpressing mice were generated by bilateral injection of adeno-associated virus vectors encoding the phosphomimetic TauS214E/T231E/S356E (Tau3E) variant into the hippocampal CA3 region of 2-month-old C57BL/6 mice. The mice received intraperitoneal rapamycin for one week. Cognitive performance was assessed using the Morris water maze. MALDI-mass spectrometry imaging was conducted to evaluate metabolic alterations in the brain tissue slices. mTOR, p70S6K, and tau phosphorylation protein expression; mitochondrial dynamics markers; and reactive oxygen species (ROS) levels were analyzed by Western blotting, immunofluorescence, and flow cytometry in HT22 cells, Tau3E mice, and postmortem AD brain tissues. ResultsPhosphorylated mTORS2448 colocalized with p-TauSer214, p-TauSer356, and p-TauThr231 in the hippocampal CA3 region of AD brains. HT22 cells and Tau3E mice exhibited increased levels of p-mTOR, p-p70S6K, and ROS production; mitochondrial fragmentation; and tau phosphorylation at Ser214, Ser356, and Thr231. Rapamycin treatment partially ameliorated cognitive deficits, reduced oxidative stress and mitochondrial dysfunction, and restored metabolic profile particularly the inosine-pentose phosphate pathway-glycolysis metabolic axis, structural lipidome axis and the neurotransmitter homeostasis. ConclusionmTOR activation contributes to site-specific tau hyperphosphorylation, mitochondrial dysfunction, and cognitive impairment. Pharmacological inhibition of mTOR by rapamycin attenuated tau pathology, regulated metabolic alterations, preserved mitochondrial homeostasis, and improved cognitive function, suggesting a potential therapeutic strategy for AD.