ABSTRACT
Deposition of fibrillar forms of amyloid ß-protein (Aß) is commonly found in patients with Alzheimer's disease (AD) associated with cognitive decline. Impaired clearance of Aß species is thought to be a major cause of late-onset sporadic AD. Aß secreted into the extracellular milieu can be cleared from the brain through multiple pathways, including cellular uptake in neuronal and non-neuronal cells. Recent studies have showed that the naturally-occurring polyphenol amentoflavone (AMF) exerts anti-amyloidogenic effects. However, its effects on metabolism and cellular clearance of Aß remain to be tested. In the present study, we demonstrated that AMF significantly increased the cellular uptake of both Aß1-40 and Aß1-42, but not inverted Aß42-1 in mouse neuronal N2a cells. Though AMF promoted internalization of cytotoxic Aß1-42, it significantly reduced cell death in our assay condition. Our data further revealed that the internalized Aß is translocated to lysosomes and undergoes enzymatic degradation. The saturable kinetic of Aß uptake and our pharmacologic experiments showed the involvement of receptor-mediated endocytosis, in part, through the class A scavenger receptors as a possible mechanism of action of AMF. Taken together, our findings indicate that AMF can lower the levels of extracellular Aß by increasing their cellular uptake and clearance, suggesting the therapeutic potential of AMF for the treatment of AD.
