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Interplay between glypican-1, amyloid-β and tau phosphorylation in human neural stem cells

Cheng, Fang LU ; Fransson, Lars Åke LU and Mani, Katrin LU orcid (2024) In Neuroscience 553. p.121-127
Abstract

Introduction: Alzheimer's disease (AD) is characterized by accumulation of amyloid beta (Aβ) and hyperphosphorylated tau (Tau-P) in the brain. Aβ enhances the activity of kinases involved in the formation of Tau-P. Phosphorylation at Thr 181 determines the propagation of multiple tau phosphorylations. Aβ is derived from the amyloid precursor protein (APP). Cleavage of APP by β-secretase also initiates release of heparan sulfate (HS) from the proteoglycan glypican-1 (GPC1). Objectives: In this study, we have explored possible connections between GPC1 expression, HS release, APP processing and Tau-P formation in human neural stem cells. Methods: GPC1 formation was suppressed by using CRISPR/Cas9 and increased by using a vector encoding... (More)

Introduction: Alzheimer's disease (AD) is characterized by accumulation of amyloid beta (Aβ) and hyperphosphorylated tau (Tau-P) in the brain. Aβ enhances the activity of kinases involved in the formation of Tau-P. Phosphorylation at Thr 181 determines the propagation of multiple tau phosphorylations. Aβ is derived from the amyloid precursor protein (APP). Cleavage of APP by β-secretase also initiates release of heparan sulfate (HS) from the proteoglycan glypican-1 (GPC1). Objectives: In this study, we have explored possible connections between GPC1 expression, HS release, APP processing and Tau-P formation in human neural stem cells. Methods: GPC1 formation was suppressed by using CRISPR/Cas9 and increased by using a vector encoding GPC1. HS release from GPC1 was increased by growing cells in medium containing Arg and ascorbate. Effects were monitored by immunofluorescence microscopy and slot immunoblotting using antibodies/antisera recognizing Aβ, GPC1, HS released from GPC1, total Tau, and Tau phosphorylated at Thr-181, 217 or 231. The latter have been used as blood biomarkers for AD. Results: Suppression of GPC1 expression resulted in increased phosphorylation at Thr 181 and Thr 217. When GPC1 was overexpressed, phosphorylation at Thr 217 decreased. Stimulation of HS release from GPC1 diminished tau phosphorylation at all of the three Thr positions, while expression of GPC1 was unaffected. Simultaneous stimulation of HS release and APP processing by the cytokine TNF-α also suppressed tau phosphorylation. Conclusion: The increased release of GPC1-derived HS may interfere with Aβ formation and/or Aβ interaction with tau.

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author
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organization
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type
Contribution to journal
publication status
published
subject
keywords
Alzheimer's disease, Amyloid beta, Heparan sulfate, Phosphorylation, Tau, Vitamin C
in
Neuroscience
volume
553
pages
7 pages
publisher
Elsevier
external identifiers
  • pmid:38992568
  • scopus:85198721661
ISSN
0306-4522
DOI
10.1016/j.neuroscience.2024.07.005
language
English
LU publication?
yes
id
7e651afb-2f13-4b98-88ce-8b5fb2d71c40
date added to LUP
2024-09-13 12:57:49
date last changed
2024-09-13 12:58:23
@article{7e651afb-2f13-4b98-88ce-8b5fb2d71c40,
  abstract     = {{<p>Introduction: Alzheimer's disease (AD) is characterized by accumulation of amyloid beta (Aβ) and hyperphosphorylated tau (Tau-P) in the brain. Aβ enhances the activity of kinases involved in the formation of Tau-P. Phosphorylation at Thr 181 determines the propagation of multiple tau phosphorylations. Aβ is derived from the amyloid precursor protein (APP). Cleavage of APP by β-secretase also initiates release of heparan sulfate (HS) from the proteoglycan glypican-1 (GPC1). Objectives: In this study, we have explored possible connections between GPC1 expression, HS release, APP processing and Tau-P formation in human neural stem cells. Methods: GPC1 formation was suppressed by using CRISPR/Cas9 and increased by using a vector encoding GPC1. HS release from GPC1 was increased by growing cells in medium containing Arg and ascorbate. Effects were monitored by immunofluorescence microscopy and slot immunoblotting using antibodies/antisera recognizing Aβ, GPC1, HS released from GPC1, total Tau, and Tau phosphorylated at Thr-181, 217 or 231. The latter have been used as blood biomarkers for AD. Results: Suppression of GPC1 expression resulted in increased phosphorylation at Thr 181 and Thr 217. When GPC1 was overexpressed, phosphorylation at Thr 217 decreased. Stimulation of HS release from GPC1 diminished tau phosphorylation at all of the three Thr positions, while expression of GPC1 was unaffected. Simultaneous stimulation of HS release and APP processing by the cytokine TNF-α also suppressed tau phosphorylation. Conclusion: The increased release of GPC1-derived HS may interfere with Aβ formation and/or Aβ interaction with tau.</p>}},
  author       = {{Cheng, Fang and Fransson, Lars Åke and Mani, Katrin}},
  issn         = {{0306-4522}},
  keywords     = {{Alzheimer's disease; Amyloid beta; Heparan sulfate; Phosphorylation; Tau; Vitamin C}},
  language     = {{eng}},
  pages        = {{121--127}},
  publisher    = {{Elsevier}},
  series       = {{Neuroscience}},
  title        = {{Interplay between glypican-1, amyloid-β and tau phosphorylation in human neural stem cells}},
  url          = {{http://dx.doi.org/10.1016/j.neuroscience.2024.07.005}},
  doi          = {{10.1016/j.neuroscience.2024.07.005}},
  volume       = {{553}},
  year         = {{2024}},
}