Mechanisms underlying large-leaf yellow tea mediated inhibition of cognitive impairment in the 5xFAD model of Alzheimer's disease

Background: Alzheimer's disease (AD) is the most common cause of dementia and is characterized by amyloid-beta (A beta) peptides and hyperphosphorylated Tau proteins. Evidence indicates that AD and type 2 diabetes mellitus (T2DM) share pathophysiological characteristics, including impaired insulin sensitivity. Large-leaf yellow tea (LYT) has been widely recognized for its health benefits, and we previously found that LYT can improve peripheral insulin resistance. Purpose: This study aimed to investigate the protective effects and underlying mechanisms of LYT in the 5xFAD mouse model of AD. Methods: HPLC and spectrophotometric methods determined the chemical composition of the LYT extract. 5xFAD mice were treated with LYT supplementation (2 and 4 mg/ml) in drinking water for six months. Barnes and Y mazes were used to evaluate cognitive function, and the open field test assessed anxiety-like behavior. Immunofluorescence, silver, and Nissl staining were used to evaluate the pathological effects of LYT extract. A FRET based assay assessed beta-site APP cleavage enzyme 1 (BACE1) activity, ELISA measured A beta levels in the brain, and Western blot analyses explored protein expression levels. Results: Our results revealed that LYT significantly attenuated memory impairment and anxiety levels and alleviated cerebral neural damage. A reduction of senile plaques was also observed in both the cortex and hippocampus. LYT significantly inhibited the activity of BACE1, which resulted in a lower A beta protein level. In addition, LYT enhanced insulin receptor substrate 1 (IRS-1)-mediated phosphorylation of phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT), further suppressed glycogen synthase kinase-3 beta (GSK3 beta), and ultimately inhibited hyperphosphorylation of the protein Tau. The inhibitory effect of the LYT extract on the phosphorylation of Tau and BACE1 activity was dose-dependent. Conclusion: LYT improves cognitive ability and reduces A beta production by inhibiting BACE1 activity. Decreases of Tau protein hyperphosphorylation upon LYT treatment appear to be associated with the regulation of the IRS-1/PI3K/AKT/GSK3 beta axis. Thus, the findings of this study also provide new evidence that LYT regulates insulin signaling pathways within the central nervous system.

Automated summary

Large-leaf yellow tea (LYT) improves cognitive ability and reduces β-amyloid (Aβ) production by inhibiting BACE1 activity. The therapeutic effects of LYT may be associated with the regulation of insulin signaling pathways.