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

Accumulation of amyloid-beta (A beta) peptide in the brain is the first critical step in the pathogenesis of Alzheimer's disease (AD). Studies in humans suggest that A beta clearance from the brain is frequently impaired in late-onset AD. A beta accumulation leads to the formation of A beta 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 A beta 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 A beta oligomerization and the deposition of amyloid plaques. In vivo microdialysis experiments also detected an accelerated rate of A beta clearance in the brain interstitial fluid, suggesting that neuronal HS either inhibited or represented an inefficient pathway for A beta 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 A beta-HSPG interactions.