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Polyphyllin I attenuates cognitive impairments and reduces AD-like pathology through CIP2A-PP2A signaling pathway in
Ying Zhou1,2, Dichen Yang3, Hao Chen3
1Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Abstract:
Polyphyllin I (PPI) is a natural phytochemical drug isolated from plants which can inhibit the proliferation of cancer cells. One of the PPI tumor-inhibitory effects is through downregulating the expression of Cancerous Inhibitor of PP2A (CIP2A), the latter, is found upregulated in Alzheimer's disease (AD) brains and participates in the development of AD. In this study, we explored the application of PPI in experimental AD treatment in CIP2A-overexpressed cells and 3XTg-AD mice. In CIP2A-overexpressed HEK293 cells or primary neurons, PPI effectively reduced CIP2A level, activated PP2A, and decreased the phosphorylation of tau/APP and the level of Aβ. Furthermore, synaptic protein levels were restored by PPI in primary neurons overexpressing CIP2A. Animal experiments in 3XTg-AD mice revealed that PPI treatment resulted in decreased CIP2A expression and PP2A re-activation. With the modification of CIP2A-PP2A signaling, the hyperphosphorylation of tau/APP and Aβ overproduction were prevented, and the cognitive impairments of 3XTg-AD mice were rescued. In summary, PPI ameliorated AD-like pathology and cognitive impairment through modulating CIP2A-PP2A signaling pathway. It may be a potential drug candidate for the treatment of AD.
Insights
Polyphyllin I (PPI) shows promise for Alzheimer's disease (AD) treatment by reducing Cancerous Inhibitor of PP2A (CIP2A) levels. This natural drug restores cognitive function and ameliorates AD pathology in preclinical models.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Alzheimer's disease (AD) is characterized by upregulated Cancerous Inhibitor of PP2A (CIP2A).
- CIP2A plays a role in AD pathogenesis, making it a potential therapeutic target.
- Polyphyllin I (PPI), a natural phytochemical, inhibits cancer cell proliferation by downregulating CIP2A.
Purpose of the Study:
- To investigate the therapeutic potential of Polyphyllin I (PPI) in Alzheimer's disease (AD).
- To evaluate the effects of PPI on CIP2A expression and related signaling pathways in AD models.
Main Methods:
- Utilized CIP2A-overexpressed HEK293 cells and primary neurons to assess PPI's molecular effects.
- Administered PPI to 3XTg-AD mice to evaluate in vivo efficacy.
- Measured CIP2A levels, PP2A activity, tau/APP phosphorylation, Aβ levels, synaptic protein expression, and cognitive function.
Main Results:
- PPI reduced CIP2A levels and activated PP2A in CIP2A-overexpressed cells and neurons.
- PPI decreased tau/APP phosphorylation and Aβ levels, while restoring synaptic proteins.
- In 3XTg-AD mice, PPI decreased CIP2A, reactivated PP2A, prevented tau/APP hyperphosphorylation and Aβ overproduction, and rescued cognitive deficits.
Conclusions:
- PPI ameliorates AD-like pathology and cognitive impairment by modulating the CIP2A-PP2A signaling pathway.
- PPI demonstrates potential as a therapeutic candidate for Alzheimer's disease treatment.
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