IJPPP Copyright © 2009-All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711
Int J Physiol Pathophysiol Pharmacol 2009;1(1):15-24.

Original Article
Amyloid-beta alters trafficking of internalized acetylcholinesterase and dextran

William Hu, Noah W. Gray, and Stephen Brimijoin

Department of Pharmacology, Mayo Clinic, Rochester, MN

Received December 18, 2008; accepted December 22, 2008; available online January 1, 2009

Abstract:  Amyloid-beta (Ab), the main peptide constituent of senile plaques, is a suspected pathogenic mediator in Alzheimer's
Disease (AD). Plaques also contain acetylcholinesterase (AChE), which may promote Ab toxicity. We recently found that Ab increased
AChE levels in neuron-like N1E.115 neuroblastoma cells by reducing AChE degradation and surface shedding. Here we show that Ab
also alters the intracellular fate of surface AChE. When surface AChE was tagged with FITC-conjugated Fasciculin II (FasII),
fluorescence gradually accumulated in intracellular particles. In the presence of extracellular Ab this accumulation increased and
shifted from the juxtanuclear zone to more peripheral cytoplasm. The cytoplasmic FasII-positive structures were positive for
Lysosomal-Associated Membrane Protein 1, identifying them as late endosomes and early lysosomes. Thus, surface AChE trafficked
into the lysosomal compartment, but further transport was impaired. Ab also affected the transport or disposition of fluorescent dextran,
an index of pinocytosis, and caused a 60% increase in intracellular accumulation similar to the lysosomotropic effects of
chloroquine. On the other hand, Ab caused no apparent changes in clathrin- and caveolaemediated endocytosis. Overall it appears that
selective alteration of endocytic mechanisms and an accumulation of organelles containing improperly processed substrates might
contribute to the neuronal damage associated with age and disease-related accumulation of neurotoxic Ab in the human brain.
(IJPPP812001).

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Address all correspondence to:
Stephen Brimijoin, PhD
Department of Pharmacology
Mayo Clinic COllege of Medicine
Rochester, MN 55905
E-mail:
brimijoi@mayo.edu