2020
DOI: 10.1074/jbc.ra119.010353
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A synthetic heparinoid blocks Tau aggregate cell uptake and amplification

Abstract: Tau aggregation underlies neurodegeneration in Alzheimer's disease and related tauopathies. We and others have proposed that transcellular propagation of pathology is mediated by Tau prions, which are ordered protein assemblies that faithfully replicate in vivo and cause specific biological effects. The prion model predicts the release of aggregates from a first-order cell and subsequent uptake into a second-order cell. The assemblies then serve as templates for their own replication, a process termed “seeding… Show more

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Cited by 25 publications
(24 citation statements)
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“…Thus, an approach to modulate tau spreading might be to use of exogenous PG mimetics, including heparin [ 289 ]. SN-13 is a heparin-derivative developed from pentasaccharide units that inhibits tau aggregate propagation in a similar way to heparin [ 290 ]. Additionally, simple heparin-like oligosaccharides bearing 2-O, 6-O, and N-sulfation can bind strongly to tau oligomers, blocking their internalization in SH-SY5Y cells [ 289 ].…”
Section: Pharmacological Modulators Of Tau Spreadingmentioning
confidence: 99%
“…Thus, an approach to modulate tau spreading might be to use of exogenous PG mimetics, including heparin [ 289 ]. SN-13 is a heparin-derivative developed from pentasaccharide units that inhibits tau aggregate propagation in a similar way to heparin [ 290 ]. Additionally, simple heparin-like oligosaccharides bearing 2-O, 6-O, and N-sulfation can bind strongly to tau oligomers, blocking their internalization in SH-SY5Y cells [ 289 ].…”
Section: Pharmacological Modulators Of Tau Spreadingmentioning
confidence: 99%
“…71 Treatment of heparin or a heparinoid compound (SN7-13) inhibits seeding by both oligomeric and fibrillar species and reduces FRET of the biosensor. 71 The development of these cellular FRET biosensor technologies provide the platforms to study the aggregation cascade of tau proteins, including monomers (intramolecular doubly labeled tau or single-molecule FRET 72 ), oligomers (intermolecular WT tau biosensor) and fibrillar species (intermolecular tauRD biosensor). Some of these systems, especially the intramolecular biosensors, have also been used to study tau-microtubule interactions [73][74][75] as well as the detachment of tau from microtubule and the subsequent formation of oligomers and aggregates.…”
Section: Flow Cytometry Based Fret Measurementmentioning
confidence: 99%
“… Weisová et al (2019) studied the mechanism of AX004, a therapeutic antibodies known to inhibit tau uptake in vivo , and determined the antibody’s mechanism was driven by disruption of the tau-HS interaction via binding to the MTBR. Stopschinski et al (2020) recently reported a synthetic heparin like oligosaccharide capable of disrupting cellular propagation of tau protein at similar activity to full length porcine derived heparin. In the long term, drugs targeting the tau HS interaction could prove to be a novel therapeutic for AD.…”
Section: Distinct Hs Sulfation Patterns Govern Tau-hs Interaction and Uptakementioning
confidence: 99%