Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Heparan Sulfate in the Amyloidosis and Inflammation of Alzheimer’s Disease
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Alzheimer’s disease (AD) is a neurodegenerative disorder, with extensive evidence implicating the misfolding, aggregation and deposition of the amyloid-β (Aβ) peptide as central to the pathogenesis. Heparan sulfate (HS) is an interactive glycosaminoglycan, attached to core proteins as HS proteoglycans (HSPGs). HSPGs are present on cell surfaces and in the extracellular matrix where they facilitate multiple signaling functions, but HS is also consistently present in all amyloid deposits, including those of AD. In amyloidosis HS has been studied as an aggregation template, promoting fibril formation and serving a scaffold function in the resulting deposits. The objective of this thesis was to assess how cell surface HS is potentially implicated in Aβ amyloidosis and the associated neuroinflammation of AD.  

In AD brain we determined that HS predominantly accumulated in Aβ deposits with dense cores and found glial-expressed HSPGs within these deposits. Aβ elevated HSPG levels in primary glial cultures, implicating activated glia as one source of the Aβ-associated HS. Next, we determined that microglial HSPGs are critical for the upregulation of interleukin-1β and tumor necrosis factor-α following exposure to lipopolysaccharide, an established inflammatory insult. Together these results raise the possibility that Aβ-induced expression of microglial HSPGs may promote neuroinflammation.  

Multiple mechanisms of Aβ toxicity have been proposed and different Aβ assemblies exert their toxicity through alternative routes. We found that three different preparations of Aβ aggregates all exhibited HS-dependent cytotoxicity, which in part correlated with Aβ internalization. Furthermore, heparin treatment attenuated Aβ cytotoxicity and uptake. In Aβ-positive AD microvasculature, HS deposited with Apolipoprotein E (ApoE) and its receptor, the low density lipoprotein receptor-related protein 1 (LRP1). In cell culture, HS and LRP1 co-operated in Aβ interactions and the addition of ApoE increased the levels of cell-associated Aβ in a HS- and LRP1-dependent manner. This ApoE-mediated increase in cell-associated Aβ may promote toxicity and vascular degeneration, but equally HS-mediated internalization of Aβ could represent a clearance route across the blood-brain-barrier.

The findings presented here illustrate multiple roles for cell-surface HSPGs in interactions relevant to the pathogenesis of AD.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2011. , 72 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 710
Keyword [en]
Alzheimer’s disease, amyloidosis, amyloid-β, apolipoprotein E, astrocytes, glia, heparanase, heparan sulfate, heparan sulfate proteoglycans, microglia, neuroinflammation
National Category
Cell and Molecular Biology Neurosciences
Research subject
Geriatrics; Cell Research; Neuroscience; Pathology
Identifiers
URN: urn:nbn:se:uu:diva-159927ISBN: 978-91-554-8183-4 (print)OAI: oai:DiVA.org:uu-159927DiVA: diva2:447498
Public defence
2011-11-24, Rudbecksalen, Rudbeck Laboratory, Dag Hammarskjölds väg 20, 75185, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2011-11-02 Created: 2011-10-11 Last updated: 2016-04-06Bibliographically approved
List of papers
1. Heparan sulfate accumulation with Abeta deposits in Alzheimer's disease and Tg2576 mice is contributed by glial cells
Open this publication in new window or tab >>Heparan sulfate accumulation with Abeta deposits in Alzheimer's disease and Tg2576 mice is contributed by glial cells
Show others...
2008 (English)In: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639, Vol. 18, no 4, 548-561 p.Article in journal (Refereed) Published
Abstract [en]

Amyloid beta-peptide (Abeta) plaques, one of the major neuropathological lesions in Alzheimer's disease (AD), can be broadly subdivided into two morphological categories: neuritic and diffuse. Heparan sulfate (HS) and HS proteoglycans (HSPGs) are codeposits of multiple amyloidoses, including AD. Although HS has been considered a limiting factor in the initiation of amyloid deposition, the pathological implications of HS in Abeta deposits of AD remain unclear. In this study, immunohistochemistry combined with fluorescence and confocal microscopy was employed to gain deeper insight into the accumulation of HS with Abeta plaques in sporadic and familial AD. Here we demonstrate that HS preferentially accumulated around the Abeta40 dense cores of neuritic plaques, but was largely absent from diffuse Abeta42 plaques, suggesting that Abeta42 deposition may occur independently of HS. A codeposition pattern of HS with Abeta deposits in Tg2576 mice was also examined. We identified the membrane-bound HSPGs, glypican-1 (GPC1) and syndecan-3 (SDC3), in glial cells associated with Abeta deposits, proximal to sites of HS accumulation. In mouse primary glial cultures, we observed increased levels of GPC1 and SDC3 following Abeta stimulation. These results suggest that HS codeposits with Abeta40 in neuritic plaques and is mainly derived from glial cells.

Keyword
b-Amyloid, glial cells, heparan sulfate
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-98662 (URN)10.1111/j.1750-3639.2008.00152.x (DOI)000259146700009 ()18422760 (PubMedID)
Available from: 2009-03-02 Created: 2009-03-02 Last updated: 2017-12-13Bibliographically approved
2. Microglial heparan sulfate proteoglycans mediate pro-inflammatory signaling
Open this publication in new window or tab >>Microglial heparan sulfate proteoglycans mediate pro-inflammatory signaling
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Microglia are the central nervous system’s (CNS) first line of defense against pathogenic insults and acute inflammatory responses are necessary for the resolution of infection. However, unregulated and/or chronic activation of microglia is associated with neurodegeneration. Heparan sulfate proteoglycans (HSPGs) have been attributed various roles in inflammation, but the possibility that HSPGs are integral to pro-inflammatory signaling mechanisms has not been fully explored. To analyze the relevance of microglial HSPGs in the pro-inflammatory response we isolated primary microglia from mice overexpressing human heparanase (Hpa-tg), the HS-degrading endoglucuronidase, and challenged them with the pro-inflammatory endotoxin lipopolysaccharide (LPS). The LPS-induced upregulation of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) was inhibited in Hpa-tg microglia, as was upregulation of the LPS-receptor CD14. Analysis of HSPG structures revealed that Hpa-tg microglia produced truncated HS chains. Importantly, co-treatment of microglia with heparin attenuated LPS-induced cytokine upregulation. Together these findings implicate microglial HSPGs as key facilitators of the pro-inflammatory response. Astrocytes constitute a critical support network in the CNS, but are also implicated in inflammation. LPS induced comparable levels of TNF-α in Hpa-tg and Ctrl astrocytes, indicating that the mechanism of HSPG-dependent inflammation is specific to microglia.  We conclude that microglial HSPGs are required for pro-inflammatory signaling events and that heparanase, through its HS-degrading activity, can regulate this mechanism.

National Category
Neurosciences Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-159923 (URN)
Available from: 2011-10-12 Created: 2011-10-11 Last updated: 2011-11-10
3. Heparan sulfate mediates amyloid-beta internalization and cytotoxicity
Open this publication in new window or tab >>Heparan sulfate mediates amyloid-beta internalization and cytotoxicity
Show others...
2010 (English)In: Glycobiology, ISSN 0959-6658, E-ISSN 1460-2423, Vol. 20, no 5, 533-541 p.Article in journal (Refereed) Published
Abstract [en]

Heparan sulfate (HS) has been found associated with amyloid deposits, including the toxic amyloid-beta (Abeta) peptide aggregates in cerebral vasculature and neuronal tissues in patients with Alzheimer's disease. However, the pathophysiological significance of the HS-Abeta interaction has remained unclear. In the present study, we applied cell models to gain insight into the roles of HS in relation to Abeta toxicity. Wild-type Chinese hamster ovary (CHO-WT) cells showed loss of viability following exposure to Abeta40, whereas the HS-deficient cell line, pgsD-677, was essentially resistant. Immunocytochemical analysis showed Abeta internalization by CHO-WT, but not pgsD-677 cells. Abeta40 toxicity was also attenuated in human embryonic kidney cells overexpressing heparanase. Finally, addition of heparin to human umbilical vein endothelial cells prevented internalization of added Abeta40 and protected against Abeta toxicity. Taken together, these findings suggest that cell-surface HS mediates Abeta internalization and toxicity.

Keyword
Aβ, cytotoxicity, heparanase, heparan sulfate, heparin
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-122999 (URN)10.1093/glycob/cwp205 (DOI)000276525700004 ()20053627 (PubMedID)
Available from: 2010-04-22 Created: 2010-04-22 Last updated: 2017-12-12Bibliographically approved
4. Apolipoprotein-E increases cell-associated amyloid-β through a heparan sulfate-dependent pathway
Open this publication in new window or tab >>Apolipoprotein-E increases cell-associated amyloid-β through a heparan sulfate-dependent pathway
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The increased risk of Alzheimer’s disease (AD) associated with specific apolipoprotein E (ApoE) isoforms appears to relate to altered amyloid-β (Aβ) homeostasis. The efficiency of Aβ clearance from the brain is reduced in the presence of the AD-associated ApoE4 isoform, which may explain the accumulation of Aβ deposits in the parenchyma and vasculature. The low density lipoprotein receptor-related protein 1 (LRP1) and heparan sulfate proteoglycans (HSPGs) are involved in Aβ uptake, with LRP1 further implicated in Aβ transcytosis across the blood brain barrier. However, both are also established ApoE receptors and function co-operatively to mediate cell interactions with lipoproteins and Aβ. Here we determined that HS, ApoE and LRP1 co-occur in Aβ40-positive microvessels of AD brain, establishing the relevance of studying interactions between these molecules. Using Chinese hamster ovary (CHO) cells deficient in HS or LRP1 we found that ApoE increases the levels of cell-associated Aβ in primarily a HSPG-dependent manner. Furthermore, in this model we found that ApoE is alternatively processed in the absence of cell surface HS, supporting a role for HSPGs in ApoE metabolism. The findings presented here raise the possibility that ApoE can increase Aβ associations with HSPGs and LRP1 in the vasculature. This may facilitate clearance, but if unbalanced could contribute to Aβ accumulation and the pathogenesis of AD.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-159926 (URN)
Available from: 2011-10-12 Created: 2011-10-11 Last updated: 2011-11-10

Open Access in DiVA

fulltext(3743 kB)919 downloads
File information
File name FULLTEXT01.pdfFile size 3743 kBChecksum SHA-512
212dd00b6af8b04c59415cb2107f76fb26842ee30285d80350be745f025429dc326671a276f63a3dd8ffa89fa9c9346dd8d3dd54274931a8f71f9de9e51dfe1f
Type fulltextMimetype application/pdf
Buy this publication >>

Search in DiVA

By author/editor
O'Callaghan, Paul
By organisation
Geriatrics
Cell and Molecular BiologyNeurosciences

Search outside of DiVA

GoogleGoogle Scholar
Total: 919 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 1239 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf