Lycium Barbarum Polysaccharides Improves Cognitive Functions in ICV-STZ-Induced Alzheimer’s Disease Mice Model by Improving the Synaptic Structural Plasticity and Regulating IRS1/PI3K/AKT Signaling Pathway

Medical Laboratory Science Geriatrics Neurology Biochemistry Bioengineering Life Sciences Immunology Medicine
Alzheimer’s disease ICV-STZ insulin resistance neurodegeneration synapse

Study on the Improvement of Cognitive Function in ICV-STZ-Induced Alzheimer’s Disease Mouse Model by Lycium Barbarum Polysaccharides

Research Background

Alzheimer’s disease (AD) is the most common neurodegenerative disease of the central nervous system, characterized by progressive cognitive impairment, memory loss, personality changes, and emotional disorders. Pathologically, AD is characterized by neuronal and synaptic degeneration, extracellular plaques composed of aggregated β-amyloid (Aβ) peptides, and intracellular neurofibrillary tangles composed of hyperphosphorylated Tau protein. In addition to known AD pathological factors, increasing evidence suggests that brain glucose/energy metabolism and insulin resistance also significantly increase the risk of dementia.

Brain insulin resistance is thought to be due to poor insulin receptor signaling, reduced brain insulin levels, and/or reduced insulin transport and utilization. This state of insulin resistance leads to changes in brain energy utilization and metabolism, ultimately resulting in AD-like pathological symptoms such as reduced synaptic plasticity, Aβ deposition, and increased Tau protein phosphorylation.

Research Objective

This study aims to elucidate the therapeutic mechanism of Lycium barbarum polysaccharides (LBP) on ICV-STZ Alzheimer’s disease model mice through the regulation of insulin resistance, IRS1/PI3K/Akt signaling pathway, and synaptic protein expression.

Research Methods

Animal Model

The subjects were three-month-old male C57BL/6J mice, grouped as follows: - Control group: ICV-ACSF injection - Model group: ICV-STZ (3mg/kg) - Low-dose LBP group: ICV-STZ + low-dose LBP (50mg/kg) - Medium-dose LBP group: ICV-STZ + medium-dose LBP (100mg/kg) - High-dose LBP group: ICV-STZ + high-dose LBP (200mg/kg) - Donepezil group: ICV-STZ + Donepezil (0.75mg/kg)

Behavioral Experiments

Y-maze and Morris water maze were used to evaluate spatial learning and memory abilities of mice, and Step-through and Step-down experiments were used to evaluate short-term learning and memory abilities. Results showed that LBP could significantly improve cognitive function in ICV-STZ mice.

Histological Analysis

Nissl staining and Thioflavin-T staining were performed in various mouse groups to assess brain tissue morphology and Aβ deposition changes. Nissl staining results showed that LBP could alleviate neuronal morphology and survival damage in hippocampal tissue of ICV-STZ mice; Thioflavin-T staining results showed that LBP could reduce Aβ plaque deposition in brain tissue of ICV-STZ mice.

Protein Expression Analysis

Western Blot was used to detect the expression of some key proteins in the hippocampus and cortex of ICV-STZ mice. Results showed that after LBP treatment, the phosphorylation levels of Tau protein at ser199, thr205, ser396, ser404 sites in cortex and hippocampus were significantly reduced.

Research Results and Discussion

Cognitive Function Improvement

  • Spatial Learning and Memory Ability: Y-maze and Morris water maze results showed that mice treated with all doses of LBP had significantly improved performance compared to the ICV-STZ group, with the high-dose group showing the most prominent effect.
  • Short-term Memory Ability: Step-through and Step-down experiments showed that LBP and Donepezil could significantly improve short-term memory ability in ICV-STZ mice.

Brain Tissue Morphology and Aβ Deposition

  • Neuronal morphology in the hippocampus and cortex of LBP group mice was significantly improved, and Aβ deposition was reduced.
  • Brain tissue of LBP-treated mice showed more organized neuronal structure and fewer Aβ-positive plaques.

Protein Expression Regulation

  • Tau Protein Phosphorylation: Western Blot results showed that LBP could reduce Tau protein phosphorylation at ser199, thr205, ser396, and ser404 sites in ICV-STZ mouse brains, reducing tau protein aggregation and neurofibrillary tangle formation.
  • GSK-3β and PP2A Expression: Compared to the ICV-STZ group, LBP increased GSK-3β expression at ser9 and tyr216 sites, but had no significant effect on PP2A levels.
  • IRS1/PI3K/Akt Signaling Pathway: LBP inhibited excessive tau protein phosphorylation in the IC-STZ model brain by regulating the IRS1/PI3K/Akt signaling pathway and downstream GSK-3β protein phosphorylation.
  • Synaptic-related Proteins: LBP increased the expression levels of synaptic-related proteins SV2A, SYP, PSD95, and Homer-1, which play crucial roles in maintaining synaptic morphology and function.

Research Conclusion

This study provides evidence that LBP can improve learning and memory abilities in ICV-STZ mice, alleviate pathological damage to brain tissue, and reduce excessive Tau protein phosphorylation by regulating the IRS1/PI3K/Akt/GSK3β signaling pathway and synaptic-related protein expression, demonstrating the potential efficacy of LBP in treating AD. Future research can further explore other neuroprotective mechanisms of LBP to demonstrate its application value in AD treatment.

Summary

This study systematically investigated the effects of Lycium Barbarum polysaccharides on ICV-STZ-induced Alzheimer’s disease mice, demonstrating its great potential as a potential drug for AD treatment. The study showed that LBP can significantly improve cognitive function in Alzheimer’s disease model mice by regulating multiple important neural signaling pathways, improving neuronal morphology, and enhancing synaptic function. Future research should continue to explore the various mechanisms and application potential of LBP in neurodegenerative diseases, striving to provide new ideas and solutions for the prevention and treatment of AD.