CIG suppresses tau pathology in a mouse model of tauopathy through regulating the activity of PP2A

抄録

Introduction: Microtubule associated protein tau plays an important role in the pathogenesis of Alzheimer's disease (AD). Transgenic mice expressing P301L mutant tau, rTg4510 mice, show significant tau pathological changes and are widely used in the studies of AD. Cornel iridoid glycoside (CIG) is the active ingredient extracted from Cornus officinalis, a traditional Chinese herb widely used for treatment of dementia and other age-related diseases in China. In our previous study, CIG could decrease the tau hyperphosphorylation in vitro and in vivo. Whether CIG shows beneficial effects on rTg4510 mouse model remains unknown.

Methods: In the present study, rTg4510 mice were treated with CIG for 3 months. The cognition and hyper-exploratory phenotypes of rTg4510 mice were evaluated after CIG treatment in this study. Western blot and immunofluorescence were performed to detect the levels of tau phosphorylation, phosphorylation related enzymes, cytoskeletal associated proteins and synaptic proteins. Serine/threonine phosphatase assay was applied to investigate the activity of PP2A.

Results: In the present study, CIG increased the spatial and working memory, improved the objective recognition memory and decreased the hyper-exploratory phenotype of rTg4510 mice. CIG was found to prevent the brain atrophy and neuronal loss. Besides, CIG elevated the expression levels of cytoskeleton associated proteins, synaptic proteins and protected the cytoskeleton. And CIG tau reduced hyperphosphorylation tau and pathological tau depositions. And CIG could increase the activity of Protein Phosphatase 2A (PP2A), a key phosphatase in dephosphorylating tau, and decrease the demethylation of PP2Ac at leucine 309 and phosphorylation at tyrosine 307. And CIG increased the ratio of leucine carboxyl methyltransferase and methylesterase, and evaluated the level of protein tyrosine phosphatase 1B (PTP1B) and Protein Phosphatase 2A Phosphatase Activator (PTPA).

Discussion: In the present study, CIG treatment improved the cognitive and psychology behaviors, prevented the brain atrophy and neuronal loss. Besides, CIG protected the cytoskeleton and synapse, by decreasing the hyperphosphorylation tau and tau pathology. And the mechanisms of reducing tau phosphorylation might due to the increase of PP2A activity and PTPA expression after CIG treatment. In conclusion, CIG might be a potential drug for AD targeting PTPA, a endogenous activator of PP2A.