THE DRUG TG REDUCING BACE1 EXPRESSION LEVEL AND PREVENTING COGNITIVE IMPAIRMENT IN ALZHEIMER'S DISEASE MICE

Alzheimer’s disease (AD) has characterized neuropathological hallmark. Soluble amyloid beta generated from amyloid precursor protein by beta- and gamma-secretase induces neuronal dysfunction and cell death. A key neuropathological event in AD is the cerebral accumulation of senile plaques formed by aggregates of amyloid-β(Aβ). Aβ results from two sequential endoproteolytic cleavages operated on the amyloid precursor protein (APP). First, β-secretase (BACE1) cleaves APP at the N-terminal end of the Aβ sequence to produce a secreted form of APP, named sAPPβ, and a C-terminal membrane-bound 99-aminoacid fragment (C99). Then, γ-secretase cleaves C99 within the transmembrane domain to release the Aβ peptides of different lengths, predominantly Aβ1-40 and Aβ1-42. By using USA FDA approved drug library, we could discover putative therapeutic chemicals by cell based assay. TG reduced the levels of BACE1 protein and mRNA in APP-SH-SY5Y cells. In order to confirm the effect of TG regulate the expression BACE1, we were produced the RFP (BACE1 expression indicator) -GFP (cell body) U2OS cell line and compared the TG and analogs. Carried out Morris Water Maze(MWM) experiment by using APP/PS1 AD model mouse. we deal with immunofluorescence assay in both region of each group mouse brain. we conducted an ELISA assay to determine quantitative changes of Aβ formation. In the RFP-GFP-U20S cell line, the expression of RFP was reduced about 20% in 1μM TG treated group comparing to the control group. The expression of BACE1 was reduced gradually. This decreasing result was confirmed in both protein and mRNA expression. BACE1 expression was best reduced when TG was treated than any analog. WT and TG 0.5mg/kg group found the platform quickly and accurately compared to other groups. In addition, WT and TG 0.5mg/kg group stayed longer in target quadrant compared to the other groups. TG significantly reduced BACE1 expression in APP/PS1 mouse brain. The amount of the Aβ42 and Aβ40 was significantly reduced in group treated with TG. We found that TG reduces BACE1 expression in vitro as well as in vivo, which means that TG can mitigate Alzheimer’s disease neuropathy and be developed as a therapeutic agent for Alzheimer’s disease.