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Morroniside-Induced PP2A Activation Antagonizes Tau Hyperphosphorylation in a Cellular Model of Neurodegeneration
Cui-cui Yang1, Xue-xian Kuai1,2, Wen-bin Gao1,3
1Department of Pharmacology, Xuanwu Hospital of Capital Medical University; Beijing Institute for Brain disorder; Beijing Engineering Research Center for Nerve System Drugs; Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing, China.
Background:
An accumulation of hyperphosphorylated tau in the brain is a hallmark of Alzheimer's disease (AD). Deficits in protein phosphatase 2A (PP2A) are associated with tau hyperphosphorylation in AD.
Objective:
To investigate the effects of morroniside (MOR), isolated from Cornus officinalis, on tau hyperphosphorylation and its underlying mechanisms related to PP2A.
Methods:
SK-N-SH cells were pretreated with 50-200 μM MOR for 24 h followed by 20 nM okadaic acid (OA) for 6 h. PP2Ac siRNA was transfected into HEK293 cells to determine the direct interaction of MOR with PP2A. Western blotting was used to measure the expression of proteins and enzymes. PP2A activity was measured by molybdenum blue spectrophotometry.
Results:
Pretreatment with MOR improved the cellular morphological damage and inhibited tau hyperphosphorylation in SK-N-SH cells induced by OA, a PP2A inhibitor. Moreover, MOR increased PP2A activity, concurrent with a decrease in the expression of demethylated PP2A at Leu309 and phosphorylated PP2A at Tyr307. MOR decreased protein phosphatase methylesterase 1 (PME-1) expression and the ratio of PME-1/leucine carboxyl methyltransferase 1 (LCMT-1). Furthermore, MOR treatment decreased the phosphorylation of Src at Tyr416, which regulates the phosphorylation of PP2A. MOR had no effect on PP2Ac expression and tau hyperphosphorylation in PP2Ac siRNA-transfected cells.
Conclusion:
MOR attenuated OA-induced tau hyperphosphorylation via PP2A activation, and its mechanism might be related to the regulation of PP2Ac post-translational modification and upstream enzymes such as Src and PME-1.
Insights
Morroniside (MOR) reduces tau hyperphosphorylation in Alzheimer's disease models by activating protein phosphatase 2A (PP2A). This natural compound may offer therapeutic benefits by restoring PP2A function and inhibiting damaging tau accumulation.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Alzheimer's disease (AD) is characterized by hyperphosphorylated tau accumulation in the brain.
- Deficits in protein phosphatase 2A (PP2A) activity are linked to tau hyperphosphorylation in AD.
Purpose of the Study:
- To investigate the effects of morroniside (MOR), a compound from Cornus officinalis, on tau hyperphosphorylation.
- To elucidate the underlying mechanisms involving PP2A.
Main Methods:
- SK-N-SH cells were treated with MOR and okadaic acid (OA), a PP2A inhibitor.
- PP2A activity was measured using molybdenum blue spectrophotometry.
- Western blotting assessed protein expression, and PP2Ac siRNA was used to confirm MOR's direct effects on PP2A.
Main Results:
- MOR treatment inhibited OA-induced tau hyperphosphorylation and improved cellular morphology.
- MOR increased PP2A activity, decreased demethylated PP2A (Leu309) and phosphorylated PP2A (Tyr307).
- MOR reduced PME-1 expression and Src phosphorylation, suggesting regulation of PP2A post-translational modification.
Conclusions:
- Morroniside attenuates tau hyperphosphorylation by activating PP2A.
- MOR's mechanism involves regulating PP2A post-translational modifications and upstream enzymes like Src and PME-1.
