Association of heparan sulfate proteoglycan with the neurofibrillary tangles of Alzheimer's Disease. J Neurosci 11: 3679-3683

Division of Neuropathology, Case Western Reserve University, Cleveland, Ohio 44106.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 12/1991; 11(11):3679-83.
Source: PubMed


The major intracytoplasmic lesion of Alzheimer's disease is the neurofibrillary tangle (NFT), which is primarily composed of paired helical filaments (PHFs). The mechanism responsible for the formation of PHFs, as well as their insolubility and apparent heterogeneity, is unknown. We found that basic fibroblast growth factor (bFGF) binds to heparinase-sensitive sites in NFTs. bFGF binding is due to a heparan sulfate proteoglycan (HSPG) immunocytochemically identified in NFTs. In the presence of polycations (e.g., Ca2+), HSPG will bind to free carboxyl groups in NFT proteins. HSPG binding may play a role in transforming normal soluble proteins into insoluble PHFs.

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    • "Different sGAG also facilitate the assembly in vitro of tau [3,4,10]. In addition Aβ [7,11] and tau aggregates [12] associate to sGAG in vivo. On the other hand, the binding of sGAG to Aβ has been found to decrease Aβ degradation [13]. "
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    ABSTRACT: Alzheimer's disease (AD) is characterized by the presence of two histopathological hallmarks; the senile plaques, or extracellular deposits mainly composed of amyloid-β peptide (Aβ), and the neurofibrillary tangles, or intraneuronal inclusions composed of hyperphosphorylated tau protein. Since Aβ aggregates are found in the pathological cases, several strategies are under way to develop drugs that interact with Aβ to reduce its assembly. One of them is 3-amino-1-propane sulfonic acid (Tramiprosate, 3-APS, Alzhemed™), that was developed as a sulfated glycosaminoglycan mimetic, that could interact with Aβ peptide, preventing its aggregation. However, little is known about the action of 3-APS on tau protein aggregation. In this work, we have tested the action of 3-APS on cell viability, microtubule network, actin organization and tau aggregation. Our results indicate that 3-APS favours tau aggregation, in tau transfected non-neuronal cells, and in neuronal cells. We also found that 3-APS does not affect the binding of tau to microtubules but may prevent the formation of tau-actin aggregates. We like to emphasize the importance of testing on both types of pathology (amyloid and tau) the potential drugs to be used for AD treatment.
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    • "In the case of assembly of tau by sGAG it is difficult to explain how a cytoplasmic protein like tau could bind to extracellular molecules like sGAG. There are two possible explanations for that interaction: a) in some pathological situations sGAG could be present in neuron cytoplasm, [39] or b) tau in damaged lysed neurons could go to the extracellular space where it can meet sGAG, to form extracellular NFT. "
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    • "Sulfated GAGs have been found in all types of amyloidosis examined [48]. Heparan sulfate (HS), proteoglycan (PG) and glycosaminoglycan (GAG) are co-localized with the fl-amyloid peptide found in senile plaques, congophilic angiopathy, and neurofibrillary tangles of Alzheimer brain as well as Down syndrome brain [32] [33] [43] [45] [46] [49]. In an immunohistochemical study, fl-amyloid peptides in the plaques of AD brain were more commonly co-localized with the GAG side chains of HS than the PG core protein [49]. "
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    ABSTRACT: beta-Amyloid peptide has been reported to be toxic to neurons in vitro and in vivo. The fragment of the beta 1-42 peptide believed to be responsible for this toxicity consists of amino acids 25 to 35. beta-amyloid protein, heparan sulfate (HS) glycosaminoglycan (GAG), and proteoglycan (PG) are all localized throughout the senile plaques found in Alzheimer's disease. Chondroitin sulfate (CS) and dermatan sulfate have also been found at the periphery of senile plaques. We have found that both HS and CS prevented neurite fragmentation and toxicity normally induced by beta 25-35. HS and CS by themselves did not have a significant influence on cell viability, indicating that their protective actions were not due to a general trophic effect. In contrast, cultures treated with HS and beta 1-42 did not show significantly reduced toxicity compared to cultures treated with beta 1-42 alone despite specific binding interactions. These data indicate that one function of GAGs in the brain may be to protect neurons from select toxic insults and injury, and additionally suggest that HS interacts differently with different beta-amyloid fragments. These data further suggest that different beta-amyloid fragments may induce distinct mechanisms of toxicity in vitro.
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