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Stimulation of β-amyloid precursor protein trafficking by insulin reduces intraneuronal β-amyloid and requires mitogen-activated protein kinase signaling

Gasparini, Laura ; Gouras, Gunnar K. LU orcid ; Wang, Rong ; Gross, Rachel S. ; Beal, M. Flint ; Greengard, Paul and Xu, Huaxi (2001) In The Journal of Neuroscience 21(8). p.2561-2570
Abstract

Alzheimer's Disease (AD) is characterized by cerebral accumulation of β-amyloid peptides (Aβ), which are proteolytically derived from β-amyloid precursor protein (βAPP). βAPP 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 sβAPP 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... (More)

Alzheimer's Disease (AD) is characterized by cerebral accumulation of β-amyloid peptides (Aβ), which are proteolytically derived from β-amyloid precursor protein (βAPP). βAPP 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 sβAPP 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 Aβ and that it does so by accelerating βAPP/Aβ trafficking from the trans-Golgi network, a major cellular site for Aβ generation, to the plasma membrane. Furthermore, insulin increases the extracellular level of Aβ both by promoting its secretion and by inhibiting its degradation via insulin-degrading enzyme. The action of insulin on βAPP 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 βAPP and Aβ trafficking in neuronal cultures.

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author
; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
subject
keywords
β-amyloid, β-amyloid precursor protein, Alzheimer's disease, Diabetes mellitus, Endoplasmic reticulum, Insulin, Intracellular trafficking, MAPK, Plasma membrane, Trans-Golgi network
in
The Journal of Neuroscience
volume
21
issue
8
pages
2561 - 2570
publisher
Society for Neuroscience
external identifiers
  • scopus:0035871641
  • pmid:11306609
ISSN
0270-6474
DOI
10.1523/JNEUROSCI.21-08-02561.2001
language
English
LU publication?
no
id
a59fc87d-6642-4c15-ae8f-e891bf353508
date added to LUP
2020-02-20 14:33:13
date last changed
2024-06-13 13:03:58
@article{a59fc87d-6642-4c15-ae8f-e891bf353508,
  abstract     = {{<p>Alzheimer's Disease (AD) is characterized by cerebral accumulation of β-amyloid peptides (Aβ), which are proteolytically derived from β-amyloid precursor protein (βAPP). βAPP 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 sβAPP 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 Aβ and that it does so by accelerating βAPP/Aβ trafficking from the trans-Golgi network, a major cellular site for Aβ generation, to the plasma membrane. Furthermore, insulin increases the extracellular level of Aβ both by promoting its secretion and by inhibiting its degradation via insulin-degrading enzyme. The action of insulin on βAPP 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 βAPP and Aβ trafficking in neuronal cultures.</p>}},
  author       = {{Gasparini, Laura and Gouras, Gunnar K. and Wang, Rong and Gross, Rachel S. and Beal, M. Flint and Greengard, Paul and Xu, Huaxi}},
  issn         = {{0270-6474}},
  keywords     = {{β-amyloid; β-amyloid precursor protein; Alzheimer's disease; Diabetes mellitus; Endoplasmic reticulum; Insulin; Intracellular trafficking; MAPK; Plasma membrane; Trans-Golgi network}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{8}},
  pages        = {{2561--2570}},
  publisher    = {{Society for Neuroscience}},
  series       = {{The Journal of Neuroscience}},
  title        = {{Stimulation of β-amyloid precursor protein trafficking by insulin reduces intraneuronal β-amyloid and requires mitogen-activated protein kinase signaling}},
  url          = {{http://dx.doi.org/10.1523/JNEUROSCI.21-08-02561.2001}},
  doi          = {{10.1523/JNEUROSCI.21-08-02561.2001}},
  volume       = {{21}},
  year         = {{2001}},
}