Neuronal heparan sulfates promote amyloid pathology by modulating brain amyloid-β clearance and aggregation in Alzheimer's disease

Chia-Chen Liu, Na Zhao, Yu Yamaguchi, John R. Cirrito, Takahisa Kanekiyo, David M. Holtzman, Guojun D Bu

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Accumulation of amyloid-β (Aβ) peptide in the brain is the first critical step in the pathogenesis of Alzheimer's disease (AD). Studies in humans suggest that Aβ clearance from the brain is frequently impaired in late-onset AD. Aβ accumulation leads to the formation of Aβ aggregates, which injure synapses and contribute to eventual neurodegeneration. Cell surface heparan sulfates (HSs), expressed on all cell types including neurons, have been implicated in several features in the pathogenesis of AD including its colocalization with amyloid plaques and modulatory role in Aβ aggregation. We show that removal of neuronal HS by conditional deletion of the Ext1 gene, which encodes an essential glycosyltransferase for HS biosynthesis, in postnatal neurons of amyloid model APP/PS1 mice led to a reduction in both Aβ oligomerization and the deposition of amyloid plaques. In vivo microdialysis experiments also detected an accelerated rate of Aβ clearance in the brain interstitial fluid, suggesting that neuronal HS either inhibited or represented an inefficient pathway for Aβ clearance. We found that the amounts of various HS proteoglycans (HSPGs) were increased in postmortem human brain tissues from AD patients, suggesting that this pathway may contribute directly to amyloid pathogenesis. Our findings have implications for AD pathogenesis and provide insight into therapeutic interventions targeting Aβ-HSPG interactions.

Original languageEnglish (US)
Article number332ra44
JournalScience Translational Medicine
Volume8
Issue number332
DOIs
StatePublished - Mar 30 2016

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Heparitin Sulfate
Amyloid
Alzheimer Disease
Pathology
Brain
Amyloid Plaques
Neurons
Heparan Sulfate Proteoglycans
Glycosyltransferases
Extracellular Fluid
Microdialysis
Gene Deletion
Proteoglycans
Synapses
Peptides

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Neuronal heparan sulfates promote amyloid pathology by modulating brain amyloid-β clearance and aggregation in Alzheimer's disease. / Liu, Chia-Chen; Zhao, Na; Yamaguchi, Yu; Cirrito, John R.; Kanekiyo, Takahisa; Holtzman, David M.; Bu, Guojun D.

In: Science Translational Medicine, Vol. 8, No. 332, 332ra44, 30.03.2016.

Research output: Contribution to journalArticle

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