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P4‐522: TYPE 2 DIABETES MELLITUS INDUCES TAU‐INDEPENDENT COGNITIVE AND SYNAPTIC DEFICITS IN A MOUSE MODEL
Author(s) -
Trujillo-Estrada Laura,
Kuang Run R.,
Da Cunha Celia,
Forner Stefania,
Martini Alessandra Cadete,
Nguyen Caroline,
Baglietto-Vargas David,
LaFerla Frank
Publication year - 2019
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2019.08.069
Subject(s) - type 2 diabetes mellitus , cognition , neuroscience , cognitive decline , dementia , diabetes mellitus , synapse , tau protein , population , pathological , affect (linguistics) , disease , psychology , endocrinology , medicine , alzheimer's disease , environmental health , communication
Background: Tau-glycan interaction mediates tau transcellular movement in the prion-like spread of tau pathology in Alzheimer’s disease (AD). Previously, we have characterized 6-O-group as an important factor for tau-glycan interaction. The role of 3-O-sulfo group, in contrast, is much harder to study, due to the lack of efficient method for 3-O-desulfation and the high level of redundancy in heparan sulfate 3-O-sulfotransferases (HS3ST) in mammalian cells. Methods: With chemically defined heparan sulfate glycan array, the Tau-glycan interaction was explored in detail. SPR, NMR and heparan sulfate (HS) deficient cell lines were used to validate and further characterize the important role of 3-O-sulfo in tau-glycan interaction. Results: Data from glycan array showed much higher tau-binding affinity with the presence of 3-O-sulfo group. SPR competition and cell surface binding assay in HS deficient cells further confirmed the important role of 3-O-sulfo group. Conclusions: 3-O-sulfo, a much less abundant sulfo group in HS, is likely to be an even more important determinant for the specificity of tau-HS interaction than 6-O-sulfo group. Our results have important implication not only for the fundamental biology of tauopathy but also for AD drug discovery aimed at disrupting the prion-like spread of tau pathology.