British journal of pharmacology · 2025
Scorpion venom heat-resistant synthetic peptide improves cognitive dysfunction of APP/PS1 mice through microglial retromer complex.
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Zhang Yue, Wu Yu-Xia, Zhang Xiao-Gang, Guo Song-Yu, He Jia, Hu Na-Na, Huang Yue-Lin, Kong Yue, Li Qi-Fa, Sui Ao-Ran, Zhu Bao-Hang, Piao Hua, Zhao Jie, Li Shao
Аннотация
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.
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.