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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.

Authors
  • Cheng, Fang1
  • Fransson, Lars-Åke1
  • Mani, Katrin1
  • 1 Department of Experimental Medical Science, Division of Neuroscience, Glycobiology Group, Lund University, Biomedical Center A13, SE-221 84 Lund, Sweden. , (Sweden)
Type
Published Article
Journal
Glycobiology
Publisher
Oxford University Press
Publication Date
Jan 05, 2021
Identifiers
DOI: 10.1093/glycob/cwaa120
PMID: 33403386
Source
Medline
Keywords
Language
English
License
Unknown

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 SDS-PAGE-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. © The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: [email protected]

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