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Cerebrovascular amyloid Angiopathy in bioengineered vessels is reduced by high-density lipoprotein particles enriched in Apolipoprotein E Robert, Jerome; Button, Emily B.; Martin, Emma M.; McAlary, Luke; Gidden, Zoe; Gilmour, Megan; Boyce, Guilaine; Caffrey, Tara M.; Agbay, Andrew; Clark, Amanda; Silverman, Judith M.; Cashman, Neil; Wellington, Cheryl L.

Abstract

Background: Several lines of evidence suggest that high-density lipoprotein (HDL) reduces Alzheimer’s disease (AD) risk by decreasing vascular beta-amyloid (Aβ) deposition and inflammation, however, the mechanisms by which HDL improve cerebrovascular functions relevant to AD remain poorly understood. Methods: Here we use a human bioengineered model of cerebral amyloid angiopathy (CAA) to define several mechanisms by which HDL reduces Aβ deposition within the vasculature and attenuates endothelial inflammation as measured by monocyte binding. Results: We demonstrate that HDL reduces vascular Aβ accumulation independently of its principal binding protein, scavenger receptor (SR)-BI, in contrast to the SR-BI-dependent mechanism by which HDL prevents Aβ-induced vascular inflammation. We describe multiple novel mechanisms by which HDL acts to reduce CAA, namely: i) altering Aβ binding to collagen-I, ii) forming a complex with Aβ that maintains its solubility, iii) lowering collagen-I protein levels produced by smooth-muscle cells (SMC), and iv) attenuating Aβ uptake into SMC that associates with reduced low density lipoprotein related protein 1 (LRP1) levels. Furthermore, we show that HDL particles enriched in apolipoprotein (apo)E appear to be the major drivers of these effects, providing new insights into the peripheral role of apoE in AD, in particular, the fraction of HDL that contains apoE. Conclusion: The findings in this study identify new mechanisms by which circulating HDL, particularly HDL particles enriched in apoE, may provide vascular resilience to Aβ and shed new light on a potential role of peripherally-acting apoE in AD.

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Title
Cerebrovascular amyloid Angiopathy in bioengineered vessels is reduced by high-density lipoprotein particles enriched in Apolipoprotein E
Creator
Robert, Jerome; Button, Emily B.; Martin, Emma M.; McAlary, Luke; Gidden, Zoe; Gilmour, Megan; Boyce, Guilaine; Caffrey, Tara M.; Agbay, Andrew; Clark, Amanda; Silverman, Judith M.; Cashman, Neil; Wellington, Cheryl L.
Contributor
Djavad Mowafaghian Centre for Brain Health; International Collaboration on Repair Discoveries
Publisher
BioMed Central
Date Issued
2020-03-25
Description
Background: Several lines of evidence suggest that high-density lipoprotein (HDL) reduces Alzheimer’s disease (AD) risk by decreasing vascular beta-amyloid (Aβ) deposition and inflammation, however, the mechanisms by which HDL improve cerebrovascular functions relevant to AD remain poorly understood. Methods: Here we use a human bioengineered model of cerebral amyloid angiopathy (CAA) to define several mechanisms by which HDL reduces Aβ deposition within the vasculature and attenuates endothelial inflammation as measured by monocyte binding. Results: We demonstrate that HDL reduces vascular Aβ accumulation independently of its principal binding protein, scavenger receptor (SR)-BI, in contrast to the SR-BI-dependent mechanism by which HDL prevents Aβ-induced vascular inflammation. We describe multiple novel mechanisms by which HDL acts to reduce CAA, namely: i) altering Aβ binding to collagen-I, ii) forming a complex with Aβ that maintains its solubility, iii) lowering collagen-I protein levels produced by smooth-muscle cells (SMC), and iv) attenuating Aβ uptake into SMC that associates with reduced low density lipoprotein related protein 1 (LRP1) levels. Furthermore, we show that HDL particles enriched in apolipoprotein (apo)E appear to be the major drivers of these effects, providing new insights into the peripheral role of apoE in AD, in particular, the fraction of HDL that contains apoE. Conclusion: The findings in this study identify new mechanisms by which circulating HDL, particularly HDL particles enriched in apoE, may provide vascular resilience to Aβ and shed new light on a potential role of peripherally-acting apoE in AD.
Subject
Alzheimer’s disease; Cerebrovasculature; High-density lipoprotein (HDL); Cerebral amyloid angiopathy (CAA); Endothelial inflammation; Apolipoprotein (apo)E; Tissue engineering
Genre
Article
Type
Text
Language
eng
Date Available
2020-03-26
Provider
Vancouver : University of British Columbia Library
Rights
Attribution 4.0 International (CC BY 4.0)
DOI
10.14288/1.0389636
URI
http://hdl.handle.net/2429/73810
Affiliation
Applied Science, Faculty of; Medicine, Faculty of; Science, Faculty of; Other UBC; Non UBC; Biomedical Engineering, School of; Medicine, Department of; Pathology and Laboratory Medicine, Department of; Physics and Astronomy, Department of
Citation
Molecular Neurodegeneration. 2020 Mar 25;15(1):23
Publisher DOI
10.1186/s13024-020-00366-8
Peer Review Status
Reviewed
Scholarly Level
Faculty
Copyright Holder
The Author(s)
Rights URI
http://creativecommons.org/licenses/by/4.0/
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Attribution 4.0 International (CC BY 4.0)