Cell-specific Nav1.6 knockdown reduced astrocyte-derived Aß by reverse Na+-Ca2+ transporter-mediated autophagy in alzheimer-like mice.

INTRODUCTION: Nav1.6 is closely related to the pathology of Alzheimer's Disease (AD), and astrocytes have recently been identified as a significant source of ß-amyloid (Aß). However, little is known about the connection between Nav1.6 and astrocyte-derived Aß. OBJECTIVE: This study explored the crucial role of Nav1.6 in mediated astrocyte-derived Aß in AD and knockdown astrocytic Nav1.6 alleviates AD progression by promoting autophagy and lysosome-APP fusion. METHODS: A mouse model for astrocytic Nav1.6 knockdown was constructed to study the effects of astrocytic Nav1.6 on amyloidosis. The role of astrocytic Nav1.6 on autophagy and lysosome-APP(amyloid precursor protein) fusion was used by transmission electron microscope, immunostaining, western blot and patch clamp. Glial cell activation was detected using immunostaining. Neuroplasticity and neural network were assessed using patch-clamp, Golgi stain and EEG recording. Behavioral experiments were performed to evaluate cognitive defects. RESULTS: Astrocytic Nav1.6 knockdown reduces amyloidosis, alleviates glial cell activation and morphological complexity, improves neuroplasticity and abnormal neural networks, as well as promotes learning and memory abilities in APP/PS1 mice. Astrocytic Nav1.6 knockdown reduces itself-derived Aß by promoting lysosome- APP fusion, which is related to attenuating reverse Na+-Ca2+ exchange current thus reducing intracellular Ca2+ to facilitate autophagic through AKT/mTOR/ULK pathway. CONCLUSION: Our findings unveil the crucial role of astrocyte-specific Nav1.6 in reducing astrocyte-derived Aß, highlighting its potential as a cell-specific target for modulating AD progression.

Scorpion venom heat-resistant synthesized peptide ameliorates epileptic seizures and imparts neuroprotection in rats mediated by NMDA receptors.

Finding new and effective natural products for designing antiepileptic drugs is highly important in the scientific community. The scorpion venom heat-resistant peptide (SVHRP) was purified from Buthus martensii Karsch scorpion venom, and subsequent analysis of the amino acid sequence facilitated the synthesis of a peptide known as scorpion venom heat-resistant synthesis peptide (SVHRSP) using a technique for peptide synthesis. Previous studies have demonstrated that the SVHRSP can inhibit neuroinflammation and provide neuroprotection. This study aimed to investigate the antiepileptic effect of SVHRSP on both acute and chronic kindling seizure models by inducing seizures in male rats through intraperitoneal administration of pentylenetetrazole (PTZ). Additionally, an N-methyl-D-aspartate (NMDA)-induced neuronal injury model was used to observe the anti-excitotoxic effect of SVHRSP in vitro. Our findings showed that treatment with SVHRSP effectively alleviated seizure severity, prolonged latency, and attenuated neuronal loss and glial cell activation. It also demonstrated the prevention of alterations in the expression levels of NMDA receptor subunits and phosphorylated p38 MAPK protein, as well as an improvement in spatial reference memory impairment during Morris water maze (MWM) testing in PTZ-kindled rats. In vitro experiments further revealed that SVHRSP was capable of attenuating neuronal action potential firing, inhibiting NMDA receptor currents and intracellular calcium overload, and reducing neuronal injury. These results suggest that the antiepileptic and neuroprotective effects of SVHRSP may be mediated through the regulation of NMDA receptor function and expression. This study provides new insight into therapeutic strategies for epilepsy.

AQP4 Aggravates Cognitive Impairment in Sepsis-Associated Encephalopathy through Inhibiting Nav 1.6-Mediated Astrocyte Autophagy.

The pathology of sepsis-associated encephalopathy (SAE) is related to astrocyte-inflammation associated with aquaporin-4 (AQP4). The aim here is to investigate the effects of AQP4 associated with SAE and reveal its underlying mechanism causing cognitive impairment. The in vivo experimental results reveal that AQP4 in peripheral blood of patients with SAE is up-regulated, also the cortical and hippocampal tissue of cecal ligation and perforation (CLP) mouse brain has significant rise in AQP4. Furthermore, the data suggest that AQP4 deletion could attenuate learning and memory impairment, attributing to activation of astrocytic autophagy, inactivation of astrocyte and downregulate the expression of proinflammatory cytokines induced by CLP or lipopolysaccharide (LPS). Furthermore, the activation effect of AQP4 knockout on CLP or LPS-induced PPAR-γ inhibiting in astrocyte is related to intracellular Ca2+ level and sodium channel activity. Learning and memory impairment in SAE mouse model are attenuated by AQP4 knockout through activating autophagy, inhibiting neuroinflammation leading to neuroprotection via down-regulation of Nav 1.6 channels in the astrocytes. This results in the reduction of Ca2+ accumulation in the cell cytosol furthermore activating the inhibition of PPAR-γ signal transduction pathway in astrocytes.

Scorpion venom heat-resistant synthetic peptide protects dopamine neurons against 6-hydroxydopamine neurotoxicity in C. elegans.

Parkinson's disease (PD) is a common neurodegenerative disease. The main pathological feature is the degeneration and loss of dopaminergic neurons in the substantia nigra, which leads to the significant decrease of dopamine content in the striatum. Our recent studies have shown that scorpion venom heat-resistant synthetic peptide (SVHRSP) have protective effects on neuroinflammation. In this study, using C. elegans induced by 6-hydroxydopamine (6-OHDA) as neurodegenerative model, we investigated the effect of SVHRSP on dopaminergic neurons neurotoxicity. Our results implied that SVHRSP treatment could improve the motor capacity in 6-OHDA-induced C. elegans and improve dopaminergic neuron mediated food sensitivity behavior. After SVHRSP treatment, dopaminergic neuron degeneration induced by 6-OHDA was significantly prevented along with a decreased α-synuclein aggregation and restored lipid deposition in C. elegans induced by 6-OHDA. We also observed the reduced levels of reactive oxygen species (ROS) after SVHRSP treatment in model-building C. elegans. In addition, the genes related to apoptosis, oxidative stress, like ctl-1, egl-1and cat-2 in C. elegans induced by 6-OHDA upregulated after treatment with SVHRSP. In conclusion, SVHRSP may impose anti-PD effect through its neuroprotective action on dopaminergic neurons. This study elucidates the effect and related mechanism of SVHRSP on PD and provides evidences for the therapeutic treatment of PD.

Scorpion Venom Heat-Resistant Synthesized Peptide Increases Stress Resistance and Extends the Lifespan of Caenorhabditis elegans via the Insulin/IGF-1-Like Signal Pathway.

Improving healthy life expectancy by targeting aging-related pathological changes has been the spotlight of geroscience. Scorpions have been used in traditional medicine in Asia and Africa for a long time. We have isolated heat-resistant peptides from scorpion venom of Buthusmartensii Karsch (SVHRP) and found that SVHRP can attenuate microglia activation and protect Caenorhabditis elegans (C. elegans) against ß-amyloid toxicity. Based on the amino acid sequence of these peptides, scorpion venom heat-resistant synthesized peptide (SVHRSP) was prepared using polypeptide synthesis technology. In the present study, we used C. elegans as a model organism to assess the longevity-related effects and underlying molecular mechanisms of SVHRSP in vivo. The results showed that SVHRSP could prolong the lifespan of worms and significantly improve the age-related physiological functions of worms. SVHRSP increases the survival rate of larvae under oxidative and heat stress and decreases the level of reactive oxygen species and fat accumulation in vivo. Using gene-specific mutation of C. elegans, we found that SVHRSP-mediated prolongation of life depends on Daf-2, Daf-16, Skn-1, and Hsf-1 genes. These results indicate that the antiaging mechanism of SVHRSP in nematodes might be mediated by the insulin/insulin-like growth factor-1 signaling pathway. Meanwhile, SVHRSP could also up-regulate the expression of stress-inducing genes Hsp-16.2, Sod-3, Gei-7, and Ctl-1 associated with aging. In general, our study may have important implications for SVHRSP to promote healthy aging and provide strategies for research and development of drugs to treat age-related diseases.