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The effect of amyloid associated proteins on the expression of genes involved in amyloid-beta clearance by adult human astrocytes

Mulder, Sandra D.; Veerhuis, Robert; Blankenstein, Marinus A. and Nielsen, Henrietta LU (2012) In Experimental Neurology 233(1). p.373-379
Abstract
Astrocytes appear to be important mediators in the clearance of amyloid beta1-42 (A beta), the key component of senile plaques characteristic of Alzheimer's disease (AD). Recently, we found the amyloid associated proteins (AAPs) alpha 1-antichymotrypsin (ACT), apolipoprotein J and E (ApoJ and ApoE) and a mixture of serum amyloid P (SAP) and C1q (SAP-C1q) to modify A beta-uptake by human astrocytes. Here we investigated the effect of oligomeric (A beta oligo) and fibrillar A beta (A beta fib), alone and in combination with a panel of AAPs on the astrocytic expression of genes proposed to be involved in A beta-uptake and degradation. Primary human astrocytes (isolated from non-demented control (n = 4) and AD patient (n = 4) brain specimens)... (More)
Astrocytes appear to be important mediators in the clearance of amyloid beta1-42 (A beta), the key component of senile plaques characteristic of Alzheimer's disease (AD). Recently, we found the amyloid associated proteins (AAPs) alpha 1-antichymotrypsin (ACT), apolipoprotein J and E (ApoJ and ApoE) and a mixture of serum amyloid P (SAP) and C1q (SAP-C1q) to modify A beta-uptake by human astrocytes. Here we investigated the effect of oligomeric (A beta oligo) and fibrillar A beta (A beta fib), alone and in combination with a panel of AAPs on the astrocytic expression of genes proposed to be involved in A beta-uptake and degradation. Primary human astrocytes (isolated from non-demented control (n = 4) and AD patient (n = 4) brain specimens) were exposed to either A beta oligo or A beta fib preparations with or without the above mentioned AAPs. Quantitative gene expression analysis of A beta-receptors Scavenger receptor B1 (SCARB1), macrophage receptor with collagenous structure (MARCO) and low density lipoprotein receptor related protein-2 (LRP2 or megalin) as well as of A beta-degrading enzymes neprilysin (NEP), insulin-degrading enzyme (IDE) and metalloproteinase-9 (MMP-9) was performed by real-time PCR. Basal expression of NEP, IDE and SCARB1 was easily detected whereas expression of MARCO, LRP2 and MMP-9 could only be detected upon pre-amplification. Basal expression of NEP, IDE and SCARB1 did not change upon exposure to A beta oligo or A beta fib alone in any of the investigated astrocyte cultures. Interestingly NEP expression was increased upon exposure to ApoE in combination with both A beta-preparations, and also SCARB1 expression was induced upon treatment with ApoE in combination with A beta fib in astrocytes from non-demented controls. Further, SAP-C1q increased SCARB1 expression in control astrocytes when combined with A beta oligo. These alterations were not found in astrocytes from AD patients. Thus, we conclude that A beta alone apparently does not affect the astrocytic expression of IDE, NEP or SCARB1. However, NEP and SCARB1 expression is increased in astrocytes from non-demented subjects when exposed to A beta combined with AAPs like ApoE. These astrocytic gene expression-regulatory mechanisms appear to be defective in AD and thus might contribute to the development and progression of AD pathology. (C) 2011 Elsevier Inc. All rights reserved. (Less)
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author
organization
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Contribution to journal
publication status
published
subject
keywords
Astrocytes, Amyloid-beta, Clearance, Neprilysin, Insulin-degrading, enzyme, MMP-9, SCARB1, MARCO, Megalin, LRP2
in
Experimental Neurology
volume
233
issue
1
pages
373 - 379
publisher
Academic Press
external identifiers
  • wos:000300123900042
  • scopus:84856221835
ISSN
0014-4886
DOI
10.1016/j.expneurol.2011.11.001
language
English
LU publication?
yes
id
1d1e160a-188d-4936-838a-e4d87bba1fa4 (old id 2390677)
date added to LUP
2012-04-02 09:24:04
date last changed
2017-07-30 03:04:17
@article{1d1e160a-188d-4936-838a-e4d87bba1fa4,
  abstract     = {Astrocytes appear to be important mediators in the clearance of amyloid beta1-42 (A beta), the key component of senile plaques characteristic of Alzheimer's disease (AD). Recently, we found the amyloid associated proteins (AAPs) alpha 1-antichymotrypsin (ACT), apolipoprotein J and E (ApoJ and ApoE) and a mixture of serum amyloid P (SAP) and C1q (SAP-C1q) to modify A beta-uptake by human astrocytes. Here we investigated the effect of oligomeric (A beta oligo) and fibrillar A beta (A beta fib), alone and in combination with a panel of AAPs on the astrocytic expression of genes proposed to be involved in A beta-uptake and degradation. Primary human astrocytes (isolated from non-demented control (n = 4) and AD patient (n = 4) brain specimens) were exposed to either A beta oligo or A beta fib preparations with or without the above mentioned AAPs. Quantitative gene expression analysis of A beta-receptors Scavenger receptor B1 (SCARB1), macrophage receptor with collagenous structure (MARCO) and low density lipoprotein receptor related protein-2 (LRP2 or megalin) as well as of A beta-degrading enzymes neprilysin (NEP), insulin-degrading enzyme (IDE) and metalloproteinase-9 (MMP-9) was performed by real-time PCR. Basal expression of NEP, IDE and SCARB1 was easily detected whereas expression of MARCO, LRP2 and MMP-9 could only be detected upon pre-amplification. Basal expression of NEP, IDE and SCARB1 did not change upon exposure to A beta oligo or A beta fib alone in any of the investigated astrocyte cultures. Interestingly NEP expression was increased upon exposure to ApoE in combination with both A beta-preparations, and also SCARB1 expression was induced upon treatment with ApoE in combination with A beta fib in astrocytes from non-demented controls. Further, SAP-C1q increased SCARB1 expression in control astrocytes when combined with A beta oligo. These alterations were not found in astrocytes from AD patients. Thus, we conclude that A beta alone apparently does not affect the astrocytic expression of IDE, NEP or SCARB1. However, NEP and SCARB1 expression is increased in astrocytes from non-demented subjects when exposed to A beta combined with AAPs like ApoE. These astrocytic gene expression-regulatory mechanisms appear to be defective in AD and thus might contribute to the development and progression of AD pathology. (C) 2011 Elsevier Inc. All rights reserved.},
  author       = {Mulder, Sandra D. and Veerhuis, Robert and Blankenstein, Marinus A. and Nielsen, Henrietta},
  issn         = {0014-4886},
  keyword      = {Astrocytes,Amyloid-beta,Clearance,Neprilysin,Insulin-degrading,enzyme,MMP-9,SCARB1,MARCO,Megalin,LRP2},
  language     = {eng},
  number       = {1},
  pages        = {373--379},
  publisher    = {Academic Press},
  series       = {Experimental Neurology},
  title        = {The effect of amyloid associated proteins on the expression of genes involved in amyloid-beta clearance by adult human astrocytes},
  url          = {http://dx.doi.org/10.1016/j.expneurol.2011.11.001},
  volume       = {233},
  year         = {2012},
}