Increased 3- O -sulfated heparan sulfate in Alzheimer’s disease brain is associated with genetic risk gene HS3ST1

Abstract

HS3ST1 is a genetic risk gene associated with Alzheimer’s disease (AD) and overexpressed in patients, but how it contributes to the disease progression is unknown. We report the analysis of brain heparan sulfate (HS) from AD and other tauopathies using a LC-MS/MS method. A specific 3- O -sulfated HS displayed sevenfold increase in the AD group ( n = 14, P < 0.0005). Analysis of the HS modified by recombinant sulfotransferases and HS from genetic knockout mice revealed that the specific 3- O -sulfated HS is made by 3- O -sulfotransferase isoform 1 (3-OST-1), which is encoded by the HS3ST1 gene. A synthetic tetradecasaccharide (14-mer) carrying the specific 3- O -sulfated domain displayed stronger inhibition for tau internalization than a 14-mer without the domain, suggesting that the 3- O -sulfated HS is used in tau cellular uptake. Our findings suggest that the overexpression of HS3ST1 gene may enhance the spread of tau pathology, uncovering a previously unidentified therapeutic target for AD.

Synthesis and Detection of BODIPY‐, Biotin‐, and 19F‐ Labeled Single‐Entity Dendritic Heparan Sulfate Mimetics

“…[32] This led us to the structure represented by Scheme 1. Synthesis of labeled derivatives starting from diethyl 3-oxopentanedioate (6). Bifunctional core 12 was synthesized through sequential coupling and deprotection steps, before maltose alkylamine 13 was attached.…”

“…compound 5, which retains the structural integrity of Tet-29 in the form of the sulfated maltose units, whilst incorporating a synthetic handle in the form of an amino group. To address issues regarding the chemical stability of fluorophores and sulfated sugars, as well as the difficult purification of highly polar compounds, a convergent synthesis that made use of the bifunctional core 12 was formulated (Scheme 1).Synthesis of the bifunctional core 12 (Scheme 1) started with the reductive amination of diethyl 3-oxopentanedioate (6) with ammonium acetate to afford diethyl 3-aminopentanedioate (7). [36] Then amide coupling of 7 with 6-azidohexanoic acid followed by deesterification gave 3-(6-azidohexanamido) pentanedioic acid (9) in a respectable yield.…”

“…HS is found at the surface of nearly all mammalian cells and has attracted attention for its multitude of roles in homeostasis and its involvement in cancer, [1,2] inflammation, [3,4] viral infections, [5] and neurodegenerative diseases. [6,7] Conversely, heparin is scarcely produced within the human body, but it is used ubiquitously in clinical settings as an anticoagulant and has been investigated for numerous other therapeutic applications. [8] Owing to their highly negatively charged structures, both HS and heparin have large protein interactomes of up to or exceeding 500 individual mammalian proteins.…”

Vascular Heparan Sulfate and Amyloid-β in Alzheimer’s Disease Patients

“…Bulk tissue analysis has determined that HS level is elevated in AD patients [24,25,49,50], but it remains unknown if HS level in cerebrovasculature is altered in the patients [33]. This was determined by the co-staining of HS and CD31 or αSMA.…”

Synthesis and Detection of BODIPY‐, Biotin‐, and 19F‐ Labeled Single‐Entity Dendritic Heparan Sulfate Mimetics

“…Heparin and heparan sulfate (HS) are natural glycosaminoglycans of significant interest for numerous applications. HS is found at the surface of nearly all mammalian cells and has attracted attention for its multitude of roles in homeostasis and its involvement in cancer, [1,2] inflammation, [3,4] viral infections, [5] and neurodegenerative diseases [6,7] . Conversely, heparin is scarcely produced within the human body, but it is used ubiquitously in clinical settings as an anticoagulant and has been investigated for numerous other therapeutic applications [8] …”