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Reversal of apolipoprotein E4-dependent or chemical-induced accumulation of APP degradation products by vitamin C-induced release of heparan sulfate from glypican-1

Cheng, Fang LU ; Fransson, Lars Åke LU and Mani, Katrin LU orcid (2021) In Glycobiology 31(7). p.800-811
Abstract
The Apolipoprotein E4 (ApoE4) genotype is the most influential risk factor for sporadic Alzheimer's disease. It appears to be associated with retarded endosome-to-autophagosome trafficking. The amyloid precursor protein (APP) and the heparan sulfate (HS)-containing proteoglycan glypican-1 (Gpc-1) are both processed in endosomes, and mutually regulated by the APP degradation products and the released HS. We have investigated APP and Gpc-1 processing in ApoE3 and ApoE4 expressing human fibroblasts, in human neural stem cells (NSC) exposed to the cholesterol transport inhibitor U18666A and in induced neurons obtained by reprogramming of ApoE fibroblasts (ApoE-iN). We have used immunofluorescence microscopy, flow cytometry, and sodium dodecyl... (More)
The Apolipoprotein E4 (ApoE4) genotype is the most influential risk factor for sporadic Alzheimer's disease. It appears to be associated with retarded endosome-to-autophagosome trafficking. The amyloid precursor protein (APP) and the heparan sulfate (HS)-containing proteoglycan glypican-1 (Gpc-1) are both processed in endosomes, and mutually regulated by the APP degradation products and the released HS. We have investigated APP and Gpc-1 processing in ApoE3 and ApoE4 expressing human fibroblasts, in human neural stem cells (NSC) exposed to the cholesterol transport inhibitor U18666A and in induced neurons obtained by reprogramming of ApoE fibroblasts (ApoE-iN). We have used immunofluorescence microscopy, flow cytometry, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis western blotting with antibodies recognizing the released HS, APP, amyloid β(Aβ), late endosomes (Rab7), autophagosomes (LC3) and neurons (Tuj1). We found that the capacity to release HS was not fully utilized in ApoE4 expressing fibroblasts and that HS-Aβ complexes accumulated in the nuclei. In ApoE3 fibroblasts, the β-cleaved APP C-terminal fragment (β-CTF) and Aβ were primarily present in late endosomes and autophagosomes. When HS release from Gpc-1 was enhanced by ascorbate in ApoE4/4 fibroblasts, there was efficient transfer of Aβ and HS from the nuclei to autophagosomes. In U18666A-treated NSC as well as in ApoE4/4-iN we repeatedly found accumulation of APP degradation products (β-CTF/Aβ). This was reversed by subsequent exposure to ascorbate or dehydroascorbic acid. (Less)
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author
; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alzheimer’s disease, apolipoprotein E, glypican-1, heparan sulfate, vitamin C
in
Glycobiology
volume
31
issue
7
pages
12 pages
publisher
Oxford University Press
external identifiers
  • pmid:33403386
  • scopus:85116958368
ISSN
1460-2423
DOI
10.1093/glycob/cwaa120
language
English
LU publication?
yes
id
e329ca21-2b39-4ff0-aade-e8ac8fe2b75f
date added to LUP
2021-11-22 14:03:00
date last changed
2024-06-01 20:20:17
@article{e329ca21-2b39-4ff0-aade-e8ac8fe2b75f,
  abstract     = {{The Apolipoprotein E4 (ApoE4) genotype is the most influential risk factor for sporadic Alzheimer's disease. It appears to be associated with retarded endosome-to-autophagosome trafficking. The amyloid precursor protein (APP) and the heparan sulfate (HS)-containing proteoglycan glypican-1 (Gpc-1) are both processed in endosomes, and mutually regulated by the APP degradation products and the released HS. We have investigated APP and Gpc-1 processing in ApoE3 and ApoE4 expressing human fibroblasts, in human neural stem cells (NSC) exposed to the cholesterol transport inhibitor U18666A and in induced neurons obtained by reprogramming of ApoE fibroblasts (ApoE-iN). We have used immunofluorescence microscopy, flow cytometry, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis western blotting with antibodies recognizing the released HS, APP, amyloid β(Aβ), late endosomes (Rab7), autophagosomes (LC3) and neurons (Tuj1). We found that the capacity to release HS was not fully utilized in ApoE4 expressing fibroblasts and that HS-Aβ complexes accumulated in the nuclei. In ApoE3 fibroblasts, the β-cleaved APP C-terminal fragment (β-CTF) and Aβ were primarily present in late endosomes and autophagosomes. When HS release from Gpc-1 was enhanced by ascorbate in ApoE4/4 fibroblasts, there was efficient transfer of Aβ and HS from the nuclei to autophagosomes. In U18666A-treated NSC as well as in ApoE4/4-iN we repeatedly found accumulation of APP degradation products (β-CTF/Aβ). This was reversed by subsequent exposure to ascorbate or dehydroascorbic acid.}},
  author       = {{Cheng, Fang and Fransson, Lars Åke and Mani, Katrin}},
  issn         = {{1460-2423}},
  keywords     = {{Alzheimer’s disease; apolipoprotein E; glypican-1; heparan sulfate; vitamin C}},
  language     = {{eng}},
  month        = {{08}},
  number       = {{7}},
  pages        = {{800--811}},
  publisher    = {{Oxford University Press}},
  series       = {{Glycobiology}},
  title        = {{Reversal of apolipoprotein E4-dependent or chemical-induced accumulation of APP degradation products by vitamin C-induced release of heparan sulfate from glypican-1}},
  url          = {{http://dx.doi.org/10.1093/glycob/cwaa120}},
  doi          = {{10.1093/glycob/cwaa120}},
  volume       = {{31}},
  year         = {{2021}},
}