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Published on: June 10, 2013
Pterosin B improves cognitive dysfunction by promoting microglia M1/M2 polarization through inhibiting Klf5/Parp14
Yan Zhang1, Ji-Cong Chen2, Jia-Hao Zheng3
1Department of Neurology, Fujian Institute of Geriatrics, Center for Cognitive Neurology, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou 350001, China; Fujian Key Laboratory of Molecular Neurology and Institute of Neuroscience, Fujian Medical University, 88 Jiaotong Road, Fuzhou 350001, China; Institute of Clinical Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou 350001, China.
Background:
Pterosin B (PB) exhibits strong neuroprotective effects in vitro, but its therapeutic effect and underlying mechanism on Alzheimer's disease (AD) remain elusive.
Purpose:
This study aimed to investigate the anti-AD effect and mechanism of PB.
Study Design:
The therapeutic effect and mechanism of PB were investigated in APP/PS1 mice and lipopolysaccharide (LPS)-induced BV-2 cells.
Methods:
After 8 weeks of oral administration of PB or donepezil, the cognitive function was assessed using behavioral tests. Pathological damage was evaluated using histological analysis and immunohistochemical staining. Flow cytometry was applied to detect M1/M2 polarization. The expression levels of glycolysis- and oxidative phosphorylation-related proteins as well as enzyme activities were determined using Western blot and biochemical kits, respectively. The levels of inflammatory cytokines and Kruppel-like factor 5 (Klf5) were measured using enzyme-linked immunosorbent assay. AD biomarkers in serum were analyzed using single-molecular array. RNA sequencing identified the downstream molecules of Klf5, and interaction was evaluated using dual-luciferase reporter assay.
Results:
Our findings demonstrated that PB effectively ameliorated cognitive impairment and reduced pathological damage in APP/PS1 mice. Furthermore, PB facilitated the transition of the phenotype of LPS-induced BV-2 cells from M1 to M2 by modulating metabolic reprogramming. Additionally, Klf5 had high expression levels in the serum of patients with AD, which strongly correlated with cognitive performance and AD biomarkers. PB downregulated Klf5 expression both in vitro and in vivo. Subsequently, poly-ADP ribosyl polymerase 14 (Parp14) was identified as a downstream molecule of Klf5 involved in regulating metabolic reprogramming, and PB regulated microglia M1/M2 polarization by inhibiting the Klf5/Parp14 pathway.
Conclusion:
The findings suggested that PB ameliorated cognitive dysfunction in AD by modulating microglia M1/M2 polarization via inhibiting Klf5/Parp14 pathway.
Insights
Pterosin B (PB) improves cognitive function and reduces Alzheimer's disease (AD) pathology by modulating microglia polarization through the Klf5/Parp14 pathway.
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Pterosin B (PB) shows in vitro neuroprotection, but its efficacy and mechanism in Alzheimer's disease (AD) are unclear.
- Investigating novel therapeutic strategies for AD is crucial due to its increasing prevalence.
Purpose of the Study:
- To elucidate the anti-AD effects of Pterosin B (PB).
- To determine the underlying molecular mechanisms of PB in Alzheimer's disease models.
Main Methods:
- PB's therapeutic effects were assessed in APP/PS1 mice and LPS-induced BV-2 cells.
- Cognitive function, pathological damage, microglia polarization, metabolic reprogramming, and key molecular pathways (Klf5/Parp14) were analyzed.
Main Results:
- PB treatment improved cognitive function and reduced neuropathology in AD mice.
- PB modulated microglia from M1 to M2 phenotype by regulating metabolic reprogramming via the Klf5/Parp14 pathway.
- Klf5 expression in AD patients correlated with cognitive decline and AD biomarkers.
Conclusions:
- Pterosin B (PB) demonstrates therapeutic potential for Alzheimer's disease (AD).
- PB ameliorates cognitive dysfunction by inhibiting the Klf5/Parp14 pathway, thereby modulating microglia M1/M2 polarization.
