The Components ofFlemingia macrophyllaAttenuate Amyloidβ-Protein Accumulation by Regulating Amyloidβ-Protein Metabolic Pathway

Yun-Lian Lin,Mine-Fong Wu,Young-Ji Shiao,Huey-Jen Tsay,Yung-Feng Liao,Chuen-Neu Wang

doi:10.1155/2012/795843

Abstract

Flemingia macrophylla (Leguminosae) is a popular traditional remedy used in Taiwan as anti-inflammatory, promoting blood circulation and antidiabetes agent. Recent study also suggested its neuroprotective activity against Alzheimer's disease. Therefore, the effects of F. macrophylla on Aβ production and degradation were studied. The effect of F. macrophylla on Aβ metabolism was detected using the cultured mouse neuroblastoma cells N2a transfected with human Swedish mutant APP (swAPP-N2a cells). The effects on Aβ degradation were evaluated on a cell-free system. An ELISA assay was applied to detect the level of Aβ1-40 and Aβ1-42. Western blots assay was employed to measure the levels of soluble amyloid precursor protein and insulin degrading enzyme (IDE). Three fractions of F. macrophylla modified Aβ accumulation by both inhibiting β-secretase and activating IDE. Three flavonoids modified Aβ accumulation by activating IDE. The activated IDE pool by the flavonoids was distinctly regulated by bacitracin (an IDE inhibitor). Furthermore, flavonoid 94-18-13 also modulates Aβ accumulation by enhancing IDE expression. In conclusion, the components of F. macrophylla possess the potential for developing new therapeutic drugs for Alzheimer's disease.

Highlights

Flemingia macrophylla (Leguminosae) is a popular traditional remedy used in Taiwan [1] and India [2]
We investigate the effect of F. macrophylla extracts or isolated pure compounds on amyloid β (Aβ) accumulation and found that they decrease extracellular accumulation of Aβ1-40 in the cultured mouse neuroblastoma cells N2a transfected with human Swedish mutant amyloid precursor protein (APP) by inhibiting β-secretase or enhancing Aβ degradation
The results showed that insulin promotes Aβ1-40 accumulation in a concentration-dependent manner

Summary

Introduction

Flemingia macrophylla (Leguminosae) is a popular traditional remedy used in Taiwan [1] and India [2]. AD is a complex mental illness characterized by the accumulation of extracellular senile plaques and intracellular neurofibrillary tangles. Senile plaques are composed of deposited Aβ, derived from the processing of amyloid precursor protein (APP) by two enzymes: β-site APP cleaving enzyme (BACE or β-secretase) and γ-secretase [7]. According to the amyloid hypothesis, abnormal accumulation of Aβ in the brain is the primary causative factor contributing to AD pathogenesis, whereby the disease process is believed to result from an imbalance between Aβ production (anabolic activity) and clearance (catabolic activity) [8,9,10]. APP molecules are cleaved by secretases at the cell surface, the Golgi complex, and along the endosomal/lysosomal pathway [11, 12]. Much more attention has been paid to abnormal Aβ production, but recently, the role of Aβ degradation in Aβ

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