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

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 (HS), expressed on all cell types including neurons, have been implicated in several features in the pathogenesis of AD including its co-localization with amyloid plaques and modulatory role in Aβ aggregation. Here, 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 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 (ISF), suggesting that neuronal HS either inhibited or represented an inefficient pathway for Aβ clearance. Interestingly, 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.

Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins

“…1) (114-116). A recent study found that ablation of HSPG in postnatal forebrain neurons of APP/PS1 mice led to a reduction in both A oligomerization and the deposition of amyloid plaques (117). These reductions were driven by an accelerated rate of A clearance from the ISF.…”

Metabolic relationship between diabetes and Alzheimer's Disease affected by Cyclo(His-Pro) plus zinc treatment

“…Amyloid plaque formation plays a pivotal role in AD pathogenesis [38]. Accumulation of β-amyloid peptides (Aβ) in the brain is the first critical step in the pathogenesis of AD [39] and is mainly due to the aggregation of Aβ which is cleaved sequentially from amyloid precursor protein (APP) by two enzymes, β-secretase and γ-secretase. The order of cleavage is very important since if α-secretase cleaves APP first, then Aβ plaques are not formed.…”

Neuroprotective Activities of Heparin, Heparinase III, and Hyaluronic Acid on the Aβ42-Treated Forebrain Spheroids Derived from Human Stem Cells

“…Chabc treatment reduced the expression of Perlecan and CSPG and altered HA expression pattern (more dotlike). Then, the derived cortical spheroid outgrowth treated with A β 42 peptide together with different ECM-related biomolecules, including Heparin (Hep, compete with HSPG-A β binding), 48,49 HepIII, Chabc, and HA, were analyzed for cell viability (Figure 4). The treatment of cells with A β 42 together with Hep, HepIII, or HA promoted cell survival, indicated by the higher cell viability (Figure 4A,B).…”

“…These results indicate that the addition of heparin to the culture attenuates the effect of A β 42 on the cell viability, which might be due to the competition of heparin with the HSPGs for binding with A β 42 peptide. 48,49 …”