Suppression of glypican-1 autodegradation by NO-deprivation correlates with nuclear accumulation of amyloid beta in normal fibroblasts

@article{Cheng2015SuppressionOG,
  title={Suppression of glypican-1 autodegradation by NO-deprivation correlates with nuclear accumulation of amyloid beta in normal fibroblasts},
  author={Fang Cheng and L A Fransson and Katrin Mani},
  journal={Glycoconjugate Journal},
  year={2015},
  volume={32},
  pages={675-684}
}
Heparan sulfate (HS)-containing, S-nitrosylated (SNO) glypican-1 (Gpc-1) releases anhydromannose-containing HS (anMan-HS) by SNO-catalyzed autodegradation in endosomes. Transport of anMan-HS to the nucleus requires processing of the amyloid precursor protein (APP) to amyloid beta peptides (Aβ). To further examine the relationship between APP and Gpc-1 processing in normal fibroblasts we have suppressed Gpc-1 autodegradation by aminoguanidine inhibition of NO synthesis and prevented lysosomal… 
Hypoxia induces NO-dependent release of heparan sulfate in fibroblasts from the Alzheimer mouse Tg2576 by activation of nitrite reduction.
TLDR
It is proposed that normoxic Tg2576 fibroblasts maintain a high level of anhydromannose-containing heparan sulfate production by a stress-activated generation of nitric oxide from endogenous nitrite, which is enhanced by hypoxia.
Reversal of apolipoprotein E4-dependent or chemical-induced accumulation of APP degradation products by vitamin C-induced release of heparan sulfate from glypican-1.
TLDR
It is found that the capacity to release HS was not fully utilized in ApoE4 expressing fibroblasts and that HS-Aᵝ complexes accumulated in the nuclei and this was reversed by subsequent exposure to ascorbate or dehydroascorbic acid.
A Method for Bridging Population-Specific Genotypes to Detect Gene Modules Associated with Alzheimer’s Disease
TLDR
This work introduces a pipeline that combines gene expression imputation with gene module discovery, including a dense gene module search and a gene set variation analysis, to address the transferability issue of gene discoveries across populations.

References

SHOWING 1-10 OF 20 REFERENCES
Rapid nuclear transit and impaired degradation of amyloid β and glypican-1-derived heparan sulfate in Tg2576 mouse fibroblasts.
TLDR
In Tg2576 MEF there is nuclear accumulation as well as secretion of Aβ and impaired degradation of HS, which is less sensitive to inhibition of NO production and copper-chelation than WT MEF.
Non-toxic amyloid beta formed in the presence of glypican-1 or its deaminatively generated heparan sulfate degradation products.
TLDR
The protection afforded by the presence of HS degradation products may reflect a normal intracellular function for the Aβ peptides.
Constitutive and vitamin C-induced, NO-catalyzed release of heparan sulfate from recycling glypican-1 in late endosomes.
TLDR
It is concluded that NO-catalyzed degradation of HS may begin in early endosome but is mainly taking place in late endosomes, and the intracellular compartments where these products are formed are identified.
Suppression of amyloid beta A11 antibody immunoreactivity by vitamin C: possible role of heparan sulfate oligosaccharides derived from glypican-1 by ascorbate-induced, nitric oxide (NO)-catalyzed degradation.
TLDR
Results support the notion that an inadequate supply of vitamin C could contribute to late onset AD in humans and speculate that temporary interaction between the Aβ domain and small, anMan-containing oligosaccharides may preclude formation of toxic Aβ oligomers.
The Amyloid Precursor Protein (APP) of Alzheimer Disease and Its Paralog, APLP2, Modulate the Cu/Zn-Nitric Oxide-catalyzed Degradation of Glypican-1 Heparan Sulfate in Vivo*
TLDR
It is proposed that the rate of autoprocessing of glypican-1 is modulated by APP and APLP2 in neurons and by APLP 2 in fibroblasts, and a functional relationship between the heparan sulfate and copper ion binding activities of APP/APLP2 is identified.
SUPPRESSION OF AMYLOID BETA A11-IMMUNOREACTIVITY BY VITAMIN C: POSSIBLE ROLE OF HEPARAN SULFATE OLIGOSACCHARIDES DERIVED FROM GLYPICAN-1 BY ASCORBATE-INDUCED, NO-CATALYZED DEGRADATION
TLDR
In the presence of ascorbate there is NO-catalyzed release of anhydromannose (anMan)-containing oligosaccharides from Gpc-1-SNO, and it is investigated whether these oligosACcharides interact with A ββ β β β during APP processing and plaque formation.
Novel aspects of glypican glycobiology
TLDR
Glypicans are involved in growth factor signalling and transport, e.g. of polyamines, and how glypican and its degradation products and the cargo exit from the recycling route is an enigma.
Nuclear Translocation Uncovers the Amyloid Peptide Aβ42 as a Regulator of Gene Transcription*♦
TLDR
It is shown that Aβ peptides varying in lengths from 38 to 43 amino acids are internalized by cultured neuroblastoma cells and can be found in the nucleus, indicating that the nuclear translocation of Aβ42 impacts gene regulation, and deleterious effects of A β42 in Alzheimer disease pathogenesis may be influenced by altering the expression profiles of disease-modifying genes.
Non-conserved, S-nitrosylated cysteines in glypican-1 react with N-unsubstituted glucosamines in heparan sulfate and catalyze deaminative cleavage.
TLDR
It is proposed that the S-nitrosocysteine residues interact with closely located GlcNH(2)/NH(3)(+) in the HS side chains of the Gpc-1 PG, and release HS fragments with reducing terminal anMan, presumably without the formation of free NO.
Alzheimer neurodegeneration, autophagy, and Abeta secretion: The ins and outs (comment on DOI 10.1002/bies.201400002)
  • R. Nixon
  • Biology
    BioEssays : news and reviews in molecular, cellular and developmental biology
  • 2014
TLDR
The hypothesis is advanced that, besides being a major lysosomal degradative process, autophagy is also a mediator of Abeta secretion and this has interesting implications that could stimulate many new paths of investigation.
...
...