Glycosaminoglycans from Alzheimer’s disease hippocampus have altered capacities to bind and regulate growth factors activities and to bind tau

Abstract

Glycosaminoglycans (GAGs), including heparan sulfates and chondroitin sulfates, are major components of the extracellular matrix. Upon interacting with heparin binding growth factors (HBGF), GAGs participate to the maintaintenance of tissue homeostasis and contribute to self-healing. Although several processes regulated by HBGF are altered in Alzheimer’s disease, it is unknown whether the brain GAG capacities to bind and regulate the function of HBGF or of other heparin binding proteins, as tau, are modified in this disease. Here, we show that total sulfated GAGs from hippocampus of Alzheimer’s disease have altered capacities to bind and potentiate the activities of growth factors including FGF-2, VEGF, and BDNF while their capacity to bind to tau is remarkable increased. Alterations of GAG structures and capacities to interact with and regulate the activity of heparin binding proteins might contribute to impaired tissue homeostasis in the Alzheimer’s disease brain.

3‐O‐Sulfation of Heparan Sulfate Enhances Tau Interaction and Cellular Uptake

“…These data conclusively demonstrate that 3‐ O ‐S modification plays a crucial role in the tau–HS interaction and tau cellular uptake. Our data provide a mechanistic rationale for the recent observation that the expression of Hs3st2 and Hs3st4 is elevated in AD brain and that HS containing GAGs isolated from AD brain exhibit enhanced tau binding …”

“…As 3‐ O ‐sulfotransferases are overexpressed in the AD brain, inhibiting the expression or activity of 3‐ O ‐sulfotransferases may represent another avenue for inhibiting the propagation of NFT pathology. Indiscriminate inhibition of Hs3st may result in significant side‐effects because 3‐ O ‐sulfation is crucial for multiple physiological interactions, such as heparin interaction with ATIII in coagulation, and HS interaction with fibroblast growth factors (FGFs) in cell growth and propagation.…”

“…However, there are seven isoforms of human Hs3st , among which Hs3st2 and Hs3st4 are specifically expressed in the brain. In addition, Hs3st2 and Hs3st4 are overexpressed in the brains of AD patients, raising the possibility that they may be specifically targeted to avoid some nonspecific effects. Although reducing the 3‐ O ‐sulfation level will not completely inhibit tau uptake, a significant delay of the spread of tau pathology and dementia can still have strong impact in patients’ quality of life and have important social and economic benefits.…”

“…In humans, 3‐O‐sulfation of HS is catalyzed by seven isoforms of 3‐ O ‐sulfotransferase ( HS3ST ): HS3ST1 , HS3ST2 , HS3ST3A , HS3ST3B , HS3ST4 , HS3ST5 , and HS3ST6 . Among these isoforms, HS3ST1 , HS3ST2 , and HS3ST5 are only expressed in the brain, with increased Hs3st2 and Hs3st4 levels in the hippocampus of AD patients . Importantly, genome‐wide genetic association (GWAS) studies have implicated HS3ST1 in AD .…”

Mechanisms of secretion and spreading of pathological tau protein

“…Some mechanistic connections have been reported between late-onset AD risk gene function and tau secretion [157]. Moreover, expression and activities of several enzymes participating in generation and modification of sulfated glycosaminoglycans, particularly heparan sulfate sulfotransferases, have been reported to be altered in AD brain and to affect accumulation of phosphorylated tau species [228,229]. While altered levels and function of HSPGs may relate to many aspects of AD pathogenesis, including ApoE function and growth factor activity in the brain, it is notable that HSPGs appear to play a key role in both secretion and uptake of pathological tau species.…”