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Cited by 27Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Oligomeric amyloid-β induces early and widespread changes to the proteome in human iPSC-derived neurons

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Sackmann, Christopher, Hallbeck, Martin·2020·Scientific Reports
DOI 10.1038/s41598-020-63398-6PMC PMC7162932
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Abstract

Alzheimer’s disease (AD) is the most common form of dementia globally and is characterized by aberrant accumulations of amyloid-beta (Aβ) and tau proteins. Oligomeric forms of these proteins are believed to be most relevant to disease progression, with oligomeric amyloid-β (oAβ) particularly implicated in AD. oAβ pathology spreads among interconnected brain regions, but how oAβ induces pathology in these previously unaffected neurons requires further study. Here, we use well characterized iPSC-derived human neurons to study the early changes to the proteome and phosphoproteome after 24 h exposure to oAβ 1-42. Using nLC-MS/MS and label-free quantification, we identified several proteins that are differentially regulated in response to acute oAβ challenge. At this early timepoint, oAβ induced the decrease of TDP-43, heterogeneous nuclear ribonucleoproteins (hnRNPs), and coatomer complex I (COPI) proteins. Conversely, increases were observed in 20 S proteasome subunits and vesicle associated proteins VAMP1/2, as well as the differential phosphorylation of tau at serine 208. These changes show that there are widespread alterations to the neuronal proteome within 24 h of oAβ uptake, including proteins previously not shown to be related to neurodegeneration. This study provides new targets for the further study of early mediators of AD pathogenesis.

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  • Evidence from AD neuronal culture models indicates that soluble Aβ oligomers induce tau hyperphosphorylation in multiple sites.

    “Interestingly, evidence from AD neuronal culture models indicate that soluble Aβ oligomers (AβOs) induce tau hyperphosphorylation in multiple sites.16,17”

    From Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer's disease (2022) · cites this paper as [17]

    The Discussion reports increased tau phosphorylation at Ser208 after oligomeric Aβ exposure, but says other canonical tau phosphorylation sites were not remarkably altered after 24 hours. Its finding is therefore contrary to the attributed claim of hyperphosphorylation at multiple sites. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Sackmann, C., & Hallbeck, M.
Affiliations
Linköping University (SE)
Corresponding author
Hallbeck, Martin
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2020-04-16
Volume
10
Issue
1
Pages
6538-6538
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-020-63398-6
PMC
PMC7162932
OpenAlex
W3016616953
Cited by
27
References
11
Citations by year
2026: 2 · 2025: 5 · 2024: 4 · 2023: 3 · 2022: 5 · 2021: 7 · 2020: 1
FWCI
2.41
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DiVA (Linkoping University) (submittedVersion, other-oa)
Funders
  • Alzheimerfonden
  • Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse
  • Vetenskapsrådet (MH: 523-2013-2735)
  • The Swedish Brain Foundation The Hans-Gabriel and Alice Trolle-Wachtmeister Foundation for medical research The Swedish Dementia Foundation
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
amyloid-beta oligomers, Alzheimer's disease, iPSC-derived neurons, proteome changes, phosphoproteome, TDP-43, heterogeneous nuclear ribonucleoproteins, 20S proteasome, tau phosphorylation, neurodegeneration
MeSH terms
Humans, Mutation, Neurons, Phosphoproteins, Phosphorylation, Phosphoserine, Protein Processing, Post-Translational, Down-Regulation, Up-Regulation, Amyloid beta-Peptides, tau Proteins, Proteome, Tandem Mass Spectrometry, Protein Multimerization, Induced Pluripotent Stem Cells

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