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Journal of Histochemistry and Cytochemistry, Vol. 50, 681-690, May 2002, Copyright © 2002, The Histochemical Society, Inc.

ARTICLE

Accumulation of the Amyloid-ß Precursor Protein in Multivesicular Body-like Organelles

Marcel M. Verbeeka,b, Irene Otte–Höllerb, Jack A.M. Fransenc, and Robert M.W. de Waalb
a Departments of Neurology, University Medical Center Nijmegen, Nijmegen, The Netherlands
b Pathology, University Medical Center Nijmegen, Nijmegen, The Netherlands
c Cell Biology and Histology, University Medical Center Nijmegen, Nijmegen, The Netherlands

Correspondence to: Marcel M. Verbeek, University Medical Center Nijmegen, Dept. of Neurology, 319 LKN, PO Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: m.verbeek@ckslkn.azn.nl

It has been suggested that the successive proteolytic events leading to the production of the amyloid-ß protein from its precursor may take place at different intracellular locations. Using cultured human leptomeningeal smooth muscle cells and brain pericytes, we modulated the intracellular localization of the amyloid-ß precursor protein (APP) to study possible effects on its processing. By using immunofluorescence and immunoelectron microscopy we demonstrated that, under normal conditions, the APP is found in small intracellular vesicles, some of which were characterized as lysosomes. Both the cytokine interferon-{gamma} and the lysosomotropic drug chloroquine, but not the cytokines interleukin (IL)-1, IL-6, or tumor necrosis factor-{alpha} (TNF-{alpha}), induced an accumulation of APP in newly formed multivesicular body-like organelles. The secretion of the amyloid-ß precursor protein was slightly reduced by interferon-{gamma} or chloroquine. Double-labeling and tracer molecule uptake experiments showed that the multivesicular body-like organelles were part of the endocytic pathway. Our findings suggest that the multivesicular body-like organelles function as an intermediate organelle in the intracellular trafficking of the APP. Accumulation of the APP in this organelle is reflected by its reduced secretion from the cell.

(J Histochem Cytochem 50:681–690, 2002)

Key Words: Alzheimer's disease, amyloid-ß precursor protein, endosomes, multivesicular bodies, pericyte, smooth muscle cell, lysosomes


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