Visualization of beta-amyloid peptide (Abeta) phagocytosis by human mononuclear phagocytes: dependency on Abeta aggregate size.
Previous studies from this laboratory have shown that human monocytes exposed to beta-amyloid peptide (Abeta) exert a graded neurotoxic response in an organotypic brain culture paradigm. Moreover, this toxicity can be reduced by compounds that inhibit cell motility and phagocytosis, suggesting that internalization of Abeta may be a requirement for neurotoxic action. To confirm that Abeta is indeed phagocytosed by monocytes and to further lay the groundwork for resolving the possible linkage between this process and neurotoxicity, we examined Abeta:monocyte interactions using immunocytochemistry and fluorescence histochemistry followed by confocal microscopy and three-dimensional image reconstruction. Internalization of Abeta was detected by 24 hr following exposure of monocytes to the purified peptide, and the relative efficacy of this process appeared to be influenced by the size of the Abeta aggregates. Specifically, smaller aggregates were observed to be more efficiently internalized, while larger Abeta masses tended to reside only on the monocyte surface, apparently bound to several monocytes at once. Both colchicine and cytochalasin D, cytoskeletal perturbants that block phagocytosis, caused Abeta to accumulate in deep pits within monocytes and inhibited complete envelopment by monocyte cytoplasm. These results suggest that monocytes can indeed phagocytose aggregates of Abeta and that this process may be critical in activating these cells to a neurocytopathic state. Accordingly, interference of Abeta phagocytosis by monocytes or monocyte-derived cells may be a novel target for therapeutic action.
Weltzien
R B
RB
Blood-Brain Barrier Laboratory, Department of Pharmacology, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
Pachter
J S
JS
D000544:Alzheimer Disease / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000502:physiology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000502:physiology*; D018613:Microscopy, Confocal; D010587:Phagocytosis / Q000502:physiology*
D016229:Amyloid beta-Peptides