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Towards Understanding the Roles of Heparan Sulfate Proteoglycans in Alzheimer’s Disease
Posted: Monday, August 25, 2014 5:45 AM
Joined: 4/24/2012
Posts: 484

Alzheimer’s disease (AD) is the most common form of dementia, characterized by progressive loss of memory and cognitive dysfunctions. A central pathological event of AD is accumulation and deposition of cytotoxic amyloid-β peptide (Aβ) in the brain parenchyma. Heparan sulfate proteoglycans (HSPGs) and the side chains heparan sulfate (HS) are found associated with Aβ deposits in the brains of AD patients and transgenic animal models of AD. A growing body of evidence from in vitro and in vivo studies suggests functional roles of HSPG/HS in Aβ pathogenesis. Although the question of “how and why HSPG/HS is codeposited with Aβ?” still remains, it is within reach to understand the mechanisms of the events. Recent progress by immunohistochemical examination with advanced antibodies shed light on molecular structures of HS codeposited with Aβ. Several recent reports have provided important new insights into the roles of HSPG in Aβ pathogenesis. Particularly, experiments on mouse models revealed indispensible functions of HSPG in modulating Aβ-associated neuroinflammation and clearance of Aβ from the brain. Application of molecules to interfere with the interaction between HS and Aβ peptides has demonstrated beneficial effects on AD mouse models. Elucidating the functions of HSPG/HS in Aβ deposition and toxicity is leading to further understanding of the complex pathology of AD. The progress is encouraging development of new treatments for AD by targeting HS-Aβ interactions.



I  would like to get some input on this hypothesis. There is a lot of smoke around heparin sulfate (HS), heparin sulfate proteoglycans and sulfate deficiency as a causal factor in AD. You may remember Dr. Seneff's work on this. But, other research is showing that HS is involved with neuroinflamation in a beneficial way by activating the immune system. In other words, when there is insult to the brain (maybe from oxidative stress, viruses, amyloid, etc.) HS is critical to enabling the immune response that counteracts it. There may be something to this. What do you all think? Here's more info:



 Heparanase overexpression impairs inflammatory response and macrophage-mediated clearance of amyloid-β in murine brain




Heparan Sulfate in the Amyloidosis and Inflammation of Alzheimer’s Disease




Lane Simonian
Posted: Monday, August 25, 2014 10:31 AM
Joined: 12/12/2011
Posts: 5140

This may be another case where a compound can have a positive or negative effect depending on its levels.  Heparan sulfate proteoglycans appear to increase the activation of various tyrosine receptor kinases and g protein-coupled receptors.  At low levels, this can lead to the alpha secretase and to the removal of amyloid.  At high levels it can lead to the beta secretase and the accumulation of amyloid.  

 2003 Aug;2:482-92.

Heparan sulphate proteoglycans in Alzheimer's disease and amyloid-related disorders.


Proteoglycans are associated with all kinds of amyloid deposits in the human body. These complex macromolecules, in particular heparan sulphate proteoglycans, have also been implicated in several features of the pathogenesis of Alzheimer's disease (AD), including the genesis of senile plaques, cerebrovascular amyloid, and neurofibrillary tangles. In this review we focus on the role of proteoglycans and glycosaminoglycans in amyloidogenesis in general and in AD in particular. Heparan sulphate proteoglycans may promote amyloid-beta peptide (Abeta) or tau fibrillisation on the one hand, and provide resistance against proteolytic breakdown on the other. Knowledge about the role of proteoglycans in AD pathology may eventually be of therapeutic use, because small polysulphated compounds, which can interfere with the interaction between proteoglycan and Abeta, have been shown to stop or even prevent amyloidogenesis.


On the other hand, other sulfur containing compounds (such as glutathione and in garlic) scavenge peroxynitrites. 

Lane Simonian
Posted: Monday, August 25, 2014 10:35 AM
Joined: 12/12/2011
Posts: 5140

Part of the problem here may be the overactivation of the immune system:


A common feature of Alzheimer's disease (AD) pathology is the abundance of activated microglia in neuritic plaques containing amyloid-beta protein (Aβ) and associated molecules including heparan sulfate proteoglycan (HSPG). Besides the role as pathological chaperone favouring amyloidogenesis, little is known about whether or not HSPG can induce microglial activation. Cultures of primary murine microglia were used to assess the effect of HSPG on production of proinflammatory molecules that are known to be present in neuritic plaques of AD.


These data demonstrate that HSPG may contribute to chronic microglial activation and neurodegeneration seen in neuritic plaques of AD.