期刊
EXPERIMENTAL NEUROLOGY
卷 233, 期 1, 页码 373-379出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2011.11.001
关键词
Astrocytes; Amyloid-beta; Clearance; Neprilysin; Insulin-degrading enzyme; MMP-9; SCARB1; MARCO; Megalin; LRP2
资金
- Stichting Dioraphte
- Swedish Tegger Foundation
- Swedish Dementia Foundation
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.
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