Astragaloside IV Improves Cognitive Impairment by Reducing β-Amyloid and Tau Protein Deposition in Hippocampal Tissue of db/db Mice: A PET/CT Imaging-Based Study.

Purpose: Diabetic Cognitive Impairment is a frequent diabetes complication with few treatments. Astragaloside IV (AS-IV), a lanosterol-derived saponin, shows significant neuroprotection. This study used PET/CT to assess the effects of AS-IV on β-amyloid (Aβ) and tau protein buildup in the hippocampus of db/db mice and to investigate the underlying mechanisms involved.

Methods: Eighteen diabetic db/db mice were divided into three groups: a model group, and two treatment groups receiving AS-IV at 20 mg/kg and 40 mg/kg (n=6 each). A control group of db/m mice (n=6) was also included. Treated mice were administered AS-IV daily, while the model and control groups were administered saline for eight weeks. Biweekly, mice were assessed for body weight and fasting blood glucose. Insulin sensitivity was tested using the OGTT, and cognitive function was evaluated with the MWM. Aβ deposition was observed with ¹⁸F-AV45 PET and Congo red staining, tau protein deposition with ¹⁸F-MK6240 PET, and neurofibrillary tangles with silver staining. TNF-α levels and proteins related to the EGFR/NF-κB pathway were analyzed in blood and hippocampal tissue.

Results: The study found that AS-IV reduced weight gain (P < 0.05), lowered fasting glucose (P < 0.01-0.001), and improved glucose tolerance (P < 0.05-0.001) in db/db mice. Behavioral tests showed that AS-IV treatment decreased escape latency (P < 0.05-0.01), increased time in the target quadrant (P < 0.05-0.001), and raised the number of platform crossings (P < 0.05-0.001). ¹⁸F-AV45 PET, ¹⁸F-MK6240 PET, Congo red staining and silver staining revealed reduced Aβ (P < 0.05-0.001) and tau protein (P < 0.01) deposits in the hippocampus. ELISA and immunofluorescence assays indicated a significant decrease in TNF-α expression in serum (P < 0.05-0.001) and hippocampus (P < 0.01-0.001), while Western blot analyses showed inhibition of the EGFR/NF-κB signaling pathway.

Conclusion: This study found that AS-IV improved cognitive function in diabetic db/db mice by reducing the buildup of Aβ and tau proteins in the hippocampus via the TNF-α-activated EGFR/NF-κB pathway.