Overexpression of Heparanase Lowers the Amyloid Burden in Amyloid-β Precursor Protein Transgenic Mice

Jendresen, Charlotte Bille; Cui, Hao; Zhang, Xiao; Vlodavsky, Israël; Nilsson, Lars; Li, Jinping

doi:10.1074/jbc.m114.600569

Cited by 44 publications

(40 citation statements)

References 33 publications

(43 reference statements)

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“…Overexpression of heparanase has been reported to reduce the amyloid load in animal models of other amyloid-related diseases, including AA amyloidosis (20) and Alzheimer disease (37). In this study, we show, for the first time, that overexpression of the HS-degrading enzyme heparanase in pancreatic islets reduces islet amyloid formation.…”

Section: Discussionmentioning

confidence: 54%

Heparan Sulfate Proteoglycans Are Important for Islet Amyloid Formation and Islet Amyloid Polypeptide-induced Apoptosis

Oskarsson

Singh

Wang

et al. 2015

Journal of Biological Chemistry

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Background: Islet amyloid causes ␤ cell death in T2D. Results: Overexpression of heparanase reduced islet amyloid formation in cultured islets, and cells lacking surface associated HS were protected against IAPP-mediated toxicity. Conclusion: IAPP fibrillation requires HSPG interaction for induction of apoptosis. Significance: Inhibition of the HS and hIAPP interaction poses a potential intervention target to prevent ␤ cell death in diabetes.

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Section: Discussionmentioning

confidence: 54%

Heparan Sulfate Proteoglycans Are Important for Islet Amyloid Formation and Islet Amyloid Polypeptide-induced Apoptosis

Oskarsson

Singh

Wang

et al. 2015

Journal of Biological Chemistry

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“…HSPGs have been shown to promote Aβ aggregation and fibril formation (16, 26, 41). Thus, we next characterized amyloid plaque load in APP/PS1 and APP/PS1; n Ext1 CKO mice by staining brain sections with Thioflavin S, a fluorescent dye that binds to amyloid fibrils.…”

Section: Resultsmentioning

confidence: 99%

“…A recent study reported that overexpression of heparanase reduces the amyloid burden in a mouse model, likely by modulating Aβ deposition (26). Here, using a conditional mouse model deficient in neuronal HS in adult brain, we bypassed the developmental effects of HS and investigated the cell type-specific roles of HS in amyloid pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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.

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“…The importance of HS in the formation of Aβ amyloids in vivo and in vitro has been highlighted by several studies. For instance, transgenic mice overexpressing heparanase showed a decreased number of Aβ amyloid plaques, without alteration on the production and proportion of Aβ40 and Aβ42 peptides . Although residues 12–18 (VHHQKLV) in Aβ40 and Aβ42 are reported as the site of interaction with HS , the anionic bridge between lysine 28 and alanine 42, only present in the Aβ42, was broken by HS .…”

Section: Heparan Sulfates In Alzheimer's Diseasementioning

confidence: 99%

The role of heparan sulfates in protein aggregation and their potential impact on neurodegeneration

et al. 2018

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Neurodegenerative disorders, such as Alzheimer's, Parkinson's, and prion diseases, are directly linked to the formation and accumulation of protein aggregates in the brain. These aggregates, principally made of proteins or peptides that clamp together after acquisition of β-folded structures, also contain heparan sulfates. Several lines of evidence suggest that heparan sulfates centrally participate in the protein aggregation process. In vitro, they trigger misfolding, oligomerization, and fibrillation of amyloidogenic proteins, such as Aβ, tau, α-synuclein, prion protein, etc. They participate in the stabilization of protein aggregates, protect them from proteolysis, and act as cell-surface receptors for the cellular uptake of proteopathic seeds during their spreading. This review focuses attention on the importance of heparan sulfates in protein aggregation in brain disorders including Alzheimer's, Parkinson's, and prion diseases. The presence of these sulfated polysaccharides in protein inclusions in vivo and their capacity to trigger protein aggregation in vitro strongly suggest that they might play critical roles in the neurodegenerative process. Further advances in glyco-neurobiology will improve our understanding of the molecular and cellular mechanisms leading to protein aggregation and neurodegeneration.

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Overexpression of Heparanase Lowers the Amyloid Burden in Amyloid-β Precursor Protein Transgenic Mice

Cited by 44 publications

References 33 publications

Heparan Sulfate Proteoglycans Are Important for Islet Amyloid Formation and Islet Amyloid Polypeptide-induced Apoptosis

Heparan Sulfate Proteoglycans Are Important for Islet Amyloid Formation and Islet Amyloid Polypeptide-induced Apoptosis

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

The role of heparan sulfates in protein aggregation and their potential impact on neurodegeneration

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