Regulation of Bace1 Mrna Expression in Alzheimer'S Disease by Green Tea Catechins and Black Tea Theaflavins

Abstract

Every 67 seconds, someone in America develops Alzheimer's disease (AD). Among the top 10 causes of death, AD is the only disease that cannot be cured, treated, or prevented. The amyloid cascade hypothesis states that amyloid-β (Aβ) protein follows a nucleation-dependent pathway to form aggregates that induce nerve damage and deterioration. Aβ monomers originate from the proteolytic cleavage of the amyloid precursor protein (APP) via sequential β-secretase-1 (BACE1) and γ-secretase cleavage. In vitro models show that the presence of Aβ leads to an upregulation of BACE1 mRNA expression, resulting in a feed-forward mechanism for the amyloidogenic cleavage of APP. Epidemiological studies have correlated diets high in green tea catechins and black tea theaflavins with a reduced incidence of AD.Previous studies in our lab demonstrated the varying inhibitory capabilities of catechins (epicatechin, epigallocatechin, epigallocatechin gallate) and theaflavins (theaflavin, theaflavin monogallate) towards Aβ oligomerization, the most toxic Aβ aggregate. This study further characterized these changes in oligomer formation as well as the antioxidant capabilities of these compounds and subsequently utilized SH-SY5Y neuroblastoma cells to determine whether catechins and theaflavins could reduce Aβ-induced upregulation of BACE1 mRNA expression. While catechins had little effect on oligomerization, theaflavins altered both the size distribution and conformation of oligomers. When SH-SY5Y cells were treated with oligomers made in the presence of compounds, epicatechin and epigallocatechin reduced BACE1 expression relative to treatment with native Aβ oligomers. When SH-SY5Y cells were treated instead with native oligomers and antioxidant-capable concentrations of compounds, both epicatechin and theaflavin reduced Aβ-induced BACE1 expression. These results indicate that the antioxidant characteristic of catechins and theaflavins may be more essential in down regulating BACE1 mRNA expression than their capability to inhibit Aβ oligomerization.