P-195: Inhibitory effect of EGCG on beta-amyloid and lipopolysaccharide induced-cognitive dysfunction and secretase activity

Abstract

Alzheimer's disease (AD) is characterized by the extracellular deposition of beta-amyloid peptide (Aβ) in cerebral plaques. Aβ is derived from the β-amyloid precursor protein (APP) by the enzymes, β and γ-secretase. Recently, secretase is an attractive drug target for AD. Compounds that alter the proteolytic cleavage of APP, including those that inhibit β- or γ-secretase activity, can reduce the production of Aβ peptides and may have therapeutic potential in the treatment of AD. We investigated possible effects of (-)-epigallocatechin-3-gallate (EGCG) on memory dysfunction caused by lipopolysaccharide (LPS) and Aβ1–42 through inhibition of secretase activities and Aβ1–42 aggregation. In vitro study To determine whether EGCG affects Aβ fibrillogenesis, we measured in vitro aggregation of Aβ in the absence and presence of EGCG by the thioflavin T method. The inhibitory effect of EGCG on the Aβ aggregation was also found by the observation of Aβ aggregation under electronic microscope. In vivo study EGCG (1 and 2%; 1.5 and 3 mg/kg) was added into the drinking water and were accessed by mouse (25∼30 g) for 3 weeks ad libitum before the induction of memory impairment mice model. The inducers (Aβ1–42 of 0.23 ng/mouse and 1 μg/mouse of LPS) and vehicle (saline) were administrated intracerebroventricularly, and the behavioral tests were started 1 day after injection. Leaning and memory capacity was determined by passive avoidance and water maze tests. Activities of β- and γ-secretase were assessed by using commercially available assay kit. EGCG reversed the LPS and Aβ1–42-induced memory dysfunction in dose dependent manner (Figure 1A and B). EGCG also dose-dependently attenuated LPS and Aβ-induced β and γ-secretase activities in cortex and hippocampus of the mice brain. These inhibitory effects are accorded well with the inhibitory effect of EGCG on the Aβ aggregation in vitro (ID50: 6.18 μg/ml) (Figure 2). Our current study shows that EGCG has recovery effect against LPS and Aβ1–42-induced memory dysfunction through inhibition of secretase activity and Aβ aggregation in addition to anti-oxidant mechanism. This study therefore suggests that EGCG may be useful agent for prevention of development or progression of AD.