Research ArticleAlzheimer’s Disease

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

Science Translational Medicine  30 Mar 2016:
Vol. 8, Issue 332, pp. 332ra44
DOI: 10.1126/scitranslmed.aad3650

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Neuronal HSPGs lay a trap for amyloid

The accumulation of neurotoxic amyloid-β (Aβ) in the brain is a pathological hallmark of Alzheimer’s disease (AD). Heparan sulfate proteoglycans (HSPGs) are abundant cell surface receptors that colocalize with amyloid plaques. Here, Liu and colleagues show that genetically engineered mice lacking heparan sulfates in forebrain neurons were protected from amyloid deposition because of a faster clearance of Aβ and reduction in Aβ aggregation. Also, the authors found that several HSPG species were increased in human AD postmortem brain tissue. These findings suggest that targeting Aβ-HSPG interactions might be an effective strategy for AD prevention and treatment.

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.

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