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Scorpion venom heat-resistant synthetic peptide improves cognitive dysfunction of APP/PS1 mice through microglial
Yue Zhang1,2, Yu-Xia Wu1,3, Xiao-Gang Zhang1,4
1Department of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, Dalian Medical University, Dalian, China.
Background And Purpose:
The abnormal accumulation of amyloid-β (Aβ) in the brain is a characteristic pathological change observed in patients with Alzheimer's disease (AD). Microglial phagocytosis, dependent on recycling through the retromer complex and cell membrane-bound receptors, plays a vital role in clearing Aβ from the brain. Previous studies have demonstrated the neurotrophic and neuroprotective effects of Scorpion Venom Heat-Resistant Synthetic Peptide (SVHRSP); however, its impacts on cognitive function remain unclear. The present study aims to investigate the impact of SVHRSP on cognitive function in APP/PS1 transgenic mice and underlying mechanisms associated with microglial retromer complex.
Experimental Approach:
SVHRSP and 3-methyladenine (3-MA) were intraperitoneally injected at 7.5 months to investigate their effects on cognitive dysfunction in APP/PS1 mice. Following behavioural testing, brain samples were harvested 24 h later for electrophysiological recordings, analysis of protein and gene expression, and histological assessment. The role of microglial retromer complex was examined using primary microglia cultures.
Key Results:
SVHRSP treatment effectively improved AD-related pathological features, including cognitive impairment, neuronal loss, impaired synaptic plasticity, neuroinflammation, and Aβ deposition in APP/PS1 mice. Both in vivo and in vitro studies revealed that SVHRSP treatment increased expression of retromer complex protein VPS35. 3-MA, a specific class III phosphoinositide 3-kinase (PI3K) inhibitor that prevents autophagosome formation, reduced retromer complex protein expression and hindered the cognitive function improvements of SVHRSP.
Conclusion And Implications:
Our findings suggest that SVHRSP may enhance microglial phagocytosis by modulating retromer complex activity, thereby alleviating Aβ accumulation and improving cognitive dysfunction in AD.
Insights
Scorpion venom peptide SVHRSP improves Alzheimer's disease symptoms in mice by enhancing microglial function. This peptide boosts retromer complex activity, reducing amyloid-beta plaques and improving cognitive deficits.
Area of Science:
- Neuroscience
- Pharmacology
- Cell Biology
Background:
- Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) accumulation.
- Microglial phagocytosis, crucial for Aβ clearance, relies on the retromer complex.
- The effects of Scorpion Venom Heat-Resistant Synthetic Peptide (SVHRSP) on cognitive function are unknown.
Purpose of the Study:
- Investigate SVHRSP's impact on cognitive function in APP/PS1 transgenic mice.
- Elucidate SVHRSP's mechanism involving the microglial retromer complex.
Main Methods:
- APP/PS1 mice and primary microglia cultures were treated with SVHRSP and 3-methyladenine (3-MA).
- Cognitive function was assessed via behavioral testing.
- Brain samples underwent electrophysiological recordings, protein/gene expression analysis, and histological assessment.
Main Results:
- SVHRSP improved cognitive impairment, neuronal loss, neuroinflammation, and Aβ deposition in APP/PS1 mice.
- SVHRSP increased retromer complex protein VPS35 expression in vivo and in vitro.
- 3-MA treatment blocked SVHRSP's cognitive benefits and reduced retromer expression.
Conclusions:
- SVHRSP enhances microglial phagocytosis by modulating retromer complex activity.
- This mechanism alleviates Aβ accumulation and improves cognitive dysfunction in Alzheimer's disease models.
