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Journal of Neuroscience, Vol 14, 3122-3138, Copyright © 1994 by Society for Neuroscience
Morphologic and biochemical analysis of the intracellular trafficking of the Alzheimer beta/A4 amyloid precursor protein
GL Caporaso, K Takei, SE Gandy, M Matteoli, O Mundigl, P Greengard and P De Camilli
Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, New York 10021.
Abnormal metabolic processing of the beta/A4 amyloid precursor protein
(APP) has been implicated in the pathogenesis of Alzheimer disease. Several
aspects of normal APP processing have been elucidated, but the precise
cellular trafficking of APP remains unclear. To investigate APP trafficking
pathways further, we have examined the subcellular distribution of APP in
rat brain tissue and a variety of cultured cell types, and correlated this
distribution with the biochemical processing of APP. In immunofluorescence
microscopy of rat brain sections, APP immunoreactivity was concentrated in
the Golgi complex and in proximal axon segments. In addition, a lower level
of punctate fluorescence was visible throughout the neuropil. By
immunoelectron microscopy of rat brain tissue fragments, APP was found
associated with Golgi elements and with medium-sized, invaginated vesicles
in both axons and dendrites. Prominent localization of APP to the Golgi
complex was also found in primary cultures of rat hippocampal neurons and
in non- neuronal cell lines. When cultured cells were treated with
brefeldin A (BFA), APP immunoreactivity changed from a Golgi-like to an
endoplasmic reticulum-like distribution. No APP was detected in the
BFA-induced reticulum identified by the transferrin receptor, indicating
that concentration of APP in the Golgi does not reflect recycling between
the trans-Golgi network and early endosomal system. In immunoblots of
BFA-treated cells, there was an accumulation of full-length APP and
inhibition of APP secretory processing. Treatment with phorbol ester
resulted in a marked elevation of APP secretion, but no obvious
redistribution of APP immunoreactivity was apparent at the light microscope
level. The lysosomotropic drug chloroquine induced accumulation of APP in
cell lysates, as seen by immunoblotting. Immunofluorescence microscopy of
chloroquine-treated cells demonstrated a colocalization of APP with the
lysosomal marker Igp 120, whereas no colocalization was seen in untreated
cells. Taken together, these results support a scheme in which APP is
concentrated in the Golgi complex as it travels through the central
vacuolar system en route to the plasma membrane for secretion of its
amino-terminal domain and/or to lysosomes for degradation.
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