Investigation of the effect of apigenin in Alzheimer's disease

Abstract

Alzheimer’s disease is a chronic neuron degeneration disease, now there are over 55 million patients all over the world, and the number of patients is increasing every year. Alzheimer’s disease has majorly been found in old people who are over 60-year-old, and the risk of Alzheimer’s disease will keep increasing with aging, the patient will gradually lose their memory and finally leading to death.

Although the molecular mechanism of Alzheimer’s disease is still not clear, some of the characteristics have been found in Alzheimer’s disease patient’s brains including amyloid plaques, neurofibrillary tangles, chronic inflammation, loss of neuronal connections, and cell death.

The precise mechanisms that link amyloid β plaques and neurofibrillary tangles, the two characteristic pathological features of Alzheimer’s disease, remain unclear. Recent findings indicate that amyloid β peptide triggers several regulators of cell cycle pathways, including transcription factors CDKs and E2F1, which cause the hyperphosphorylation of tau protein. Nevertheless, the exact signaling pathways that result from amyloid β-induced cell cycle dysregulation are yet to be revealed. Our recent research reveals that E2F1, which is a transcription factor essential for cell cycle progression, DNA damage response, and apoptosis, and is inactive in adults, is amplified in Alzheimer's disease patients' brains and in APP transgenic mice. It plays a vital part in the relationship between amyloid β and tau hyperphosphorylation. The downregulation of E2F1 safeguards against neuronal death triggered by amyloid β peptides and reverses memory impairment in both amyloid β1-42 and tau C. elegans models of Alzheimer's disease. This indicates E2F1's significant role in the amyloid β-tau toxicity pathway's execution. Mechanistically, E2F1 is upregulated by amyloid β, which, in turn, stimulates the induction of Pax6 and c-Myb. Pax6 serves as a direct

target of E2F1 and its downstream target c-Myb. Additionally, E2F1 governs the transcription of GSK-3β, a kinase that plays a role in tau hyperphosphorylation and the formation of neurofibrillary tangles. Furthermore, GSK-3β phosphorylates tau at Ser356, Ser396 and Ser404.

Apigenin is a natural compound, it has been found can inhibit the expression of E2F1 and protect neurons from damage, but the previous research has not provided the mechanism, so here, we used Apigenin in our Alzheimer’s disease models to investigate the possible mechanism of Apigenin effects in Alzheimer’s disease.

In this research, we found that Apigenin could affect in Alzheimer’s disease model, after Apigenin treatment, the expression of both protein and mRNA levels are down-regulated in N2a-APP Swedish cell line, and further, the hyperphosphorylation of tau decreased at the sites of p-tau 231, 262, 396, which could participate the folding of the protein tau and the forming of neurofibrillary tangles, and we further over-expression the E2F1, we found that after we overexpression E2F1, the expression of GSK3β is accompanied to increase. After cell research, we used Apigenin to treat the 5xFAD mice, we found that the Apigenin treatment has the effects of ameliorating and prevention in Alzheimer’s disease, and the E2F1-GSK3β pathway and inflammation factors like TNFα are also down-regulated after Apigenin treatment in mice brain.