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The Journal of Neuroscience, April 15, 2001, 21(8):2561-2570
Stimulation of  -Amyloid Precursor Protein Trafficking by
Insulin Reduces Intraneuronal -Amyloid and Requires
Mitogen-Activated Protein Kinase Signaling
Laura
Gasparini1, 3, 4,
Gunnar K.
Gouras1, 3,
Rong
Wang2,
Rachel S.
Gross1,
M. Flint
Beal3,
Paul
Greengard1, and
Huaxi
Xu1
1 Laboratory of Molecular and Cellular Neuroscience,
Fisher Center for Research on Alzheimer Disease, and
2 Laboratory for Mass Spectrometry, The Rockefeller
University, New York, New York 10021, 3 Department of
Neurology and Neuroscience, Weill Medical College of Cornell
University, New York, New York 10021, and 4 Neurobiology
Laboratory, IRCCS Centro San Giovanni di Dio-Fatebenefratelli,
Brescia, Italy
Alzheimer's Disease (AD) is characterized by cerebral accumulation
of  -amyloid peptides (A), which are proteolytically derived from
-amyloid precursor protein (APP). APP metabolism is highly regulated via various signal transduction systems, e.g., several serine/threonine kinases and phosphatases. Several growth factors known
to act via receptor tyrosine kinases also have been demonstrated to regulate sAPP secretion. Among these receptors, insulin and insulin-like growth factor-1 receptors are highly expressed in brain,
especially in hippocampus and cortex. Emerging evidence indicates that
insulin has important functions in brain regions involved in learning
and memory. Here we present evidence that insulin significantly reduces
intracellular accumulation of A and that it does so by accelerating
APP/A trafficking from the trans-Golgi network, a
major cellular site for A generation, to the plasma membrane.
Furthermore, insulin increases the extracellular level of A both by
promoting its secretion and by inhibiting its degradation via
insulin-degrading enzyme. The action of insulin on APP metabolism is
mediated via a receptor tyrosine kinase/mitogen-activated protein (MAP)
kinase kinase pathway. The results suggest cell biological and signal
transduction mechanisms by which insulin modulates APP and A
trafficking in neuronal cultures.
Key words:
-amyloid; -amyloid precursor protein; insulin; MAPK; Alzheimer's disease; diabetes mellitus; intracellular
trafficking; endoplasmic reticulum; trans-Golgi network; plasma membrane
Copyright © 2001 Society for Neuroscience 0270-6474/01/2182561-10$05.00/0
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|
|
|
|
|
|
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|
|
|
|
|
|
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73(3):
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|
|
|
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276(39):
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|
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