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J Biol Chem, Vol. 273, Issue 18, 11100-11106, May 1, 1998
From the The amyloid precursor superfamily is composed of
three highly conserved transmembrane glycoproteins, the amyloid
precursor protein (APP) and amyloid precursor-like proteins 1 and 2 (APLP1, APLP2), whose functions are unknown. Proteolytic cleavage of
APP yields the
Post-translational Processing and Turnover Kinetics of
Presynaptically Targeted Amyloid Precursor Superfamily Proteins in
the Central Nervous System
,¶,
,, and**
INSERM U334, Service Hospitalier
Frédéric Joliot, Commissariat à l'Energie Atomique,
DSV/DRM, Orsay, France, ¶ Laboratorio de Metabolismo e Biochimica
Patologica, Istituto Superiore di Sanità, Rome, Italy,
Neuropathology Laboratory, Johns Hopkins University School of
Medicine, Baltimore, Maryland, and ** CEA-CNRS URA 2210, Service
Hospitalier Frederic Joliot, DRM/DSV, Orsay, France
A4 peptide, the major component of cerebral amyloid in Alzheimer's disease. Here we show that five post-translationally modified, full-length species of APP and APLP2 (but not APLP1) arrive
at the mature presynaptic terminal in the fastest wave of axonal
transport and are subsequently rapidly cleared (mean half-life of
3.5 h). Rapid turnover of presynaptic APP and APLP2 occurs
independently of visual activity. Turnover of the most rapidly arriving
APP species was accompanied by a delayed accumulation of a 120-kDa, APP
fragment lacking the C terminus, consistent with presynaptic APP
turnover via constitutive proteolysis. Turnover of APLP2 was not
accompanied by detectable APLP2 fragment peptides, suggesting either
that APLP2 either is more rapidly degraded than is APP or is
retrogradely transported shortly after reaching the terminus. A single
150-kDa APLP2 species containing the Kunitz protease inhibitor domain
is the major amyloid precursor superfamily protein transported to the
presynapse. Presynaptic APP and APLP2 are sialylated and
N- and O-glycosylated, and some also carry chondroitin sulfate glycosaminoglycan and/or dermatan sulfate glycosaminoglycan. The rapid kinetics for turnover of APP and APLP2
predict a sensitive balance of synthesis, transport, and elimination
rates that may be critical to normal neuronal functions and metabolic
fates of these proteins.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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