Deposition of amyloid fibrils promotes cell-surface accumulation of amyloid β precursor protein

Abstract

Amyloid β protein (Aβ) deposition and neuronal degeneration are characteristic pathological features of Alzheimer's disease (AD). In vitro, Aβ fibrils (fAβ) induce neuronal degeneration reminiscent to AD, but the mechanism of neurotoxicity is unknown. Here we show that amyloid fibrils increase the level of cell-surface full-length amyloid β precursor protein (h-AβPP) and secreted AβPP (s-AβPP). Pulse-chase analysis indicated that fAβ selectively inhibited the turnover of cell-surface AβPP, without altering its intracellular levels. FAβ-induced AβPP accumulation was not abrogated by cycloheximide, suggesting that increased protein synthesis is not critically required. Aβ fibrils sequester s-AβPP from the culture medium and promote its accumulation at the cell surface, indicating that binding of Aβ fibrils mediates AβPP accumulation. A time course analysis of Aβ treatment showed that AβPP level is elevated before significant cell death can be detected, while other toxic insults do not augment AβPP level, suggesting that AβPP may be specifically involved in early stages of Aβ-induced neurodegeneration. Finally, Aβ fibrils promote clustering of h-AβPP in abnormal focal adhesion-like (FA-like) structures that mediate neuronal dystrophy, increasing its association with the cytoskeleton. These results indicate that the interaction of Aβ fibrils with AβPP is an early event in the mechanism of Aβ-induced neurodegeneration that may play a significant role in AD pathogenesis.