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Journal of Neuroscience, Vol 11, 3783-3793, Copyright © 1991 by Society for Neuroscience
Processing of beta-amyloid precursor protein in microglia and astrocytes favors an internal localization over constitutive secretion
C Haass, AY Hung and DJ Selkoe
Department of Neurology, Harvard Medical School, Boston, Massachusetts.
Microglial cells and astrocytes are closely associated with nearly all
compact deposits of the amyloid beta-protein found in the senile plaques
characteristic of Alzheimer's disease and trisomy 21. The biosynthesis and
metabolic fate of the beta-amyloid precursor protein (beta APP) in
astrocytes has not been characterized, and its identification in microglia
has not been described. Here, we report the expression of beta APP by
astrocytes and microglia in primary cultures of cerebral cortex from
newborn rats. Using metabolic labeling followed by immunoprecipitation, we
show that both astrocytes and microglia express substantial amounts of the
major isoforms of beta APP. This is confirmed by PCR-mediated amplification
of the corresponding mRNAs, showing that all three major transcripts (beta
APP695, beta APP751, and beta APP770) are present in relatively equal
amounts. Despite rapid turnover of the precursor, astrocytes and microglia
show a reduced production of soluble fragments of beta APP compared to
cells transfected with beta APP cDNAs. The relative amount of soluble beta
APP molecules generated is both cell type and isoform specific.
Immunocytochemistry reveals that full-length beta APP is located in
internal membranous vesicles, with only very little insertion at the cell
surface. The latter data are in agreement with the reduced ability of
microglia and astrocytes to cleave the beta APP into soluble derivatives.
Our findings indicate that both astrocytes and microglia strongly express
all three major forms of beta APP but apparently process these molecules by
an alternative pathway that generates very small amounts of soluble beta
APP. The immunocytochemical localization and the biochemical data lead to
the suggestion that beta APP may not function principally as a cell surface
or secreted protein in vivo but may have an important intracellular
function.
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