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Clusterin levels are increased in Alzheimer's disease and influence the regional distribution of Aβ

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Clusterin levels are increased in Alzheimer's disease and influence the regional distribution of Aβ. / Miners, J Scott; Clarke, Polly; Love, Seth.

In: Brain Pathology, Vol. 27, No. 3, 05.2017, p. 305–313.

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@article{3dba1c2f8df345fb8b8bfb1cd5a5d8f4,
title = "Clusterin levels are increased in Alzheimer's disease and influence the regional distribution of Aβ",
abstract = "Clusterin, also known as apoJ, is a lipoprotein abundantly expressed within the CNS. It regulates Aβ fibril formation and toxicity and facilitates amyloid-β (Aβ) transport across the blood-brain barrier. Genome-wide association studies have shown variations in the clusterin gene (CLU) to influence the risk of developing sporadic Alzheimer's disease (AD). To explore whether clusterin modulates the regional deposition of Aβ, we measured levels of soluble (NP40-extracted) and insoluble (guanidine-HCl-extracted) clusterin, Aβ40 and Aβ42 by sandwich ELISA in brain regions with a predilection for amyloid pathology - mid-frontal cortex (MF), cingulate cortex (CC), parahippocampal cortex (PH) - and regions with little or no pathology - thalamus (TH) and white matter (WM). Clusterin level was highest in regions with plaque pathology (MF, CC, PH and PC), approximately mirroring the regional distribution of Aβ. It was significantly higher in AD than controls, and correlated positively with Aβ42 and insoluble Aβ40. Soluble clusterin level rose significantly with severity of cerebral amyloid angiopathy (CAA), and in MF and PC regions was highest in APOE ε4 homozygotes. In the TH and WM (areas with little amyloid pathology) clusterin was unaltered in AD and did not correlate with Aβ level. There was a significant positive correlation between the concentration of clusterin and the regional levels of insoluble Aβ42; however, the molar ratio of clusterin:Aβ42 declined with insoluble Aβ42 level in a region-dependent manner, being lowest in regions with predilection for Aβ plaque pathology. Under physiological conditions clusterin reduces aggregation and promotes clearance of Aβ. Our findings indicate that in AD, clusterin increases, particularly in regions with most abundant Aβ, but because the increase does not match the rising level of Aβ42, the molar ratio of clusterin:Aβ42 in those regions falls, probably contributing to Aβ deposition within the tissue. This article is protected by copyright. All rights reserved.",
keywords = "Alzheimer’s disease, clusterin, apoJ, amyloid-β, amyloid-β clearance, plaque, cerebral amyloid angiopathy",
author = "Miners, {J Scott} and Polly Clarke and Seth Love",
note = "{\circledC} 2016 International Society of Neuropathology.",
year = "2017",
month = "5",
doi = "10.1111/bpa.12392",
language = "English",
volume = "27",
pages = "305–313",
journal = "Brain Pathology",
issn = "1015-6305",
publisher = "Wiley",
number = "3",

}

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TY - JOUR

T1 - Clusterin levels are increased in Alzheimer's disease and influence the regional distribution of Aβ

AU - Miners, J Scott

AU - Clarke, Polly

AU - Love, Seth

N1 - © 2016 International Society of Neuropathology.

PY - 2017/5

Y1 - 2017/5

N2 - Clusterin, also known as apoJ, is a lipoprotein abundantly expressed within the CNS. It regulates Aβ fibril formation and toxicity and facilitates amyloid-β (Aβ) transport across the blood-brain barrier. Genome-wide association studies have shown variations in the clusterin gene (CLU) to influence the risk of developing sporadic Alzheimer's disease (AD). To explore whether clusterin modulates the regional deposition of Aβ, we measured levels of soluble (NP40-extracted) and insoluble (guanidine-HCl-extracted) clusterin, Aβ40 and Aβ42 by sandwich ELISA in brain regions with a predilection for amyloid pathology - mid-frontal cortex (MF), cingulate cortex (CC), parahippocampal cortex (PH) - and regions with little or no pathology - thalamus (TH) and white matter (WM). Clusterin level was highest in regions with plaque pathology (MF, CC, PH and PC), approximately mirroring the regional distribution of Aβ. It was significantly higher in AD than controls, and correlated positively with Aβ42 and insoluble Aβ40. Soluble clusterin level rose significantly with severity of cerebral amyloid angiopathy (CAA), and in MF and PC regions was highest in APOE ε4 homozygotes. In the TH and WM (areas with little amyloid pathology) clusterin was unaltered in AD and did not correlate with Aβ level. There was a significant positive correlation between the concentration of clusterin and the regional levels of insoluble Aβ42; however, the molar ratio of clusterin:Aβ42 declined with insoluble Aβ42 level in a region-dependent manner, being lowest in regions with predilection for Aβ plaque pathology. Under physiological conditions clusterin reduces aggregation and promotes clearance of Aβ. Our findings indicate that in AD, clusterin increases, particularly in regions with most abundant Aβ, but because the increase does not match the rising level of Aβ42, the molar ratio of clusterin:Aβ42 in those regions falls, probably contributing to Aβ deposition within the tissue. This article is protected by copyright. All rights reserved.

AB - Clusterin, also known as apoJ, is a lipoprotein abundantly expressed within the CNS. It regulates Aβ fibril formation and toxicity and facilitates amyloid-β (Aβ) transport across the blood-brain barrier. Genome-wide association studies have shown variations in the clusterin gene (CLU) to influence the risk of developing sporadic Alzheimer's disease (AD). To explore whether clusterin modulates the regional deposition of Aβ, we measured levels of soluble (NP40-extracted) and insoluble (guanidine-HCl-extracted) clusterin, Aβ40 and Aβ42 by sandwich ELISA in brain regions with a predilection for amyloid pathology - mid-frontal cortex (MF), cingulate cortex (CC), parahippocampal cortex (PH) - and regions with little or no pathology - thalamus (TH) and white matter (WM). Clusterin level was highest in regions with plaque pathology (MF, CC, PH and PC), approximately mirroring the regional distribution of Aβ. It was significantly higher in AD than controls, and correlated positively with Aβ42 and insoluble Aβ40. Soluble clusterin level rose significantly with severity of cerebral amyloid angiopathy (CAA), and in MF and PC regions was highest in APOE ε4 homozygotes. In the TH and WM (areas with little amyloid pathology) clusterin was unaltered in AD and did not correlate with Aβ level. There was a significant positive correlation between the concentration of clusterin and the regional levels of insoluble Aβ42; however, the molar ratio of clusterin:Aβ42 declined with insoluble Aβ42 level in a region-dependent manner, being lowest in regions with predilection for Aβ plaque pathology. Under physiological conditions clusterin reduces aggregation and promotes clearance of Aβ. Our findings indicate that in AD, clusterin increases, particularly in regions with most abundant Aβ, but because the increase does not match the rising level of Aβ42, the molar ratio of clusterin:Aβ42 in those regions falls, probably contributing to Aβ deposition within the tissue. This article is protected by copyright. All rights reserved.

KW - Alzheimer’s disease

KW - clusterin

KW - apoJ

KW - amyloid-β

KW - amyloid-β clearance

KW - plaque

KW - cerebral amyloid angiopathy

U2 - 10.1111/bpa.12392

DO - 10.1111/bpa.12392

M3 - Article

C2 - 27248362

VL - 27

SP - 305

EP - 313

JO - Brain Pathology

JF - Brain Pathology

SN - 1015-6305

IS - 3

ER -