Deposition of amyloid fibrils promotes cell-surface accumulation of amyloid beta precursor protein.
Amyloid beta protein (Abeta) deposition and neuronal degeneration are characteristic pathological features of Alzheimer's disease (AD). In vitro, Abeta fibrils (fAbeta) 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 beta precursor protein (h-AbetaPP) and secreted AbetaPP (s-AbetaPP). Pulse-chase analysis indicated that fAbeta selectively inhibited the turnover of cell-surface AbetaPP, without altering its intracellular levels. FAbeta-induced AbetaPP accumulation was not abrogated by cycloheximide, suggesting that increased protein synthesis is not critically required. Abeta fibrils sequester s-AbetaPP from the culture medium and promote its accumulation at the cell surface, indicating that binding of Abeta fibrils mediates AbetaPP accumulation. A time course analysis of Abeta treatment showed that AbetaPP level is elevated before significant cell death can be detected, while other toxic insults do not augment AbetaPP level, suggesting that AbetaPP may be specifically involved in early stages of Abeta-induced neurodegeneration. Finally, Abeta fibrils promote clustering of h-AbetaPP 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 Abeta fibrils with AbetaPP is an early event in the mechanism of Abeta-induced neurodegeneration that may play a significant role in AD pathogenesis.
Heredia
Lorena
L
Laboratory of Experimental Neuropathology, Instituto de Investigación Médica Mercedes y Martín Ferreyra-INIMEC/CONICET, Córdoba, 5000 Argentina.
Lin
Rong
R
Vigo
Francisco Solá
FS
Kedikian
Gabriela
G
Busciglio
Jorge
J
Lorenzo
Alfredo
A
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D022001:Focal Adhesions / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051381:Rats
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins