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Cited by 40Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration Mechanisms

Signaling via the p75 neurotrophin receptor facilitates amyloid-β-induced dendritic spine pathology

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Patnaik, Abhisarika, Zagrebelsky, Marta, Korte, Martin, Holz, Andreas·2020·Scientific Reports
DOI 10.1038/s41598-020-70153-4PMC PMC7415136
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Abstract

Synapse and dendritic spine loss induced by amyloid-β oligomers is one of the main hallmarks of the early phases of Alzheimer’s disease (AD) and is directly correlated with the cognitive decline typical of this pathology. The p75 neurotrophin receptor (p75 NTR) binds amyloid-β oligomers in the nM range. While it was shown that µM concentrations of amyloid-β mediate cell death, the role and intracellular signaling of p75 NTR for dendritic spine pathology induced by sublethal concentrations of amyloid-β has not been analyzed. We describe here p75 NTR as a crucial binding partner in mediating effects of soluble amyloid-β oligomers on dendritic spine density and structure in non-apoptotic hippocampal neurons. Removing or over-expressing p75 NTR in neurons rescues or exacerbates the typical loss of dendritic spines and their structural alterations observed upon treatment with nM concentrations of amyloid-β oligomers. Moreover, we show that binding of amyloid-β oligomers to p75 NTR activates the RhoA/ROCK signaling cascade resulting in the fast stabilization of the actin spinoskeleton. Our results describe a role for p75 NTR and downstream signaling events triggered by binding of amyloid-β oligomers and causing dendritic spine pathology. These observations further our understanding of the molecular mechanisms underlying one of the main early neuropathological hallmarks of AD.

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  • Aβ activates RhoA by binding to p75NTR, and inhibition of this receptor or RhoA directly prevents the deleterious effects of Aβ in hippocampal neurons.

    “Aβ activates RhoA by binding to the p75 neurotrophin receptor (p75NTR), and inhibition of this receptor or RhoA directly prevents the deleterious effects of Aβ in hippocampal neurons [186,196].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [196]

    The Results sections on RhoA activation and dendritic spine morphology report that Aβ1–42 activates RhoA in p75NTR-competent hippocampal cultures, and that p75NTR deletion or blocking its downstream signaling protects against Aβ-induced spine changes. The paper tested a peptide that inhibits p75NTR-mediated RhoA activation and an inhibitor of ROCK, not direct inhibition of RhoA. Its demonstrated protection concerns dendritic spine pathology, rather than all deleterious effects of Aβ. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Inhibition of p75NTR-mediated RhoA activation with the TAT-Pep5 peptide or Y-27632-mediated ROCK inhibition protects against oligomeric Aβ-induced spine loss in hippocampal neurons.

    “Inhibition of p75NTR-mediated RhoA activation with the TAT-Pep5 peptide or Y-27632-mediated ROCK inhibition protected against oligomeric Aβ-induced spine loss in hippocampal neurons [196].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [196]

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Authors
Patnaik, A., Zagrebelsky, M., Korte, M., & Holz, A.
Affiliations
  • Technische Universität Braunschweig (DE)
  • Helmholtz Centre for Infection Research (DE)
Corresponding author
Holz, Andreas
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2020-08-07
Volume
10
Issue
1
Pages
13322-13322
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-020-70153-4
PMC
PMC7415136
OpenAlex
W3047779032
Cited by
40
References
11
Citations by year
2026: 7 · 2025: 6 · 2024: 4 · 2023: 6 · 2022: 12 · 2021: 5
FWCI
3.35
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digitale Bibliothek Braunschweig (Verbundzentrale Göttingen (VZG)) (submittedVersion, cc-by)
  • HZI (Helmholtz Centre for Infection Research) (submittedVersion, cc-by)
Funders
  • German Academic Exchange Service
  • European Union Joint Program–Neurodegenerative Disease (JPND) consortium InCure
  • Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - SFB 854 (97850925)
  • Immunology and Inflammation Initiative of the Helmholtz Association
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
p75 neurotrophin receptor, amyloid-beta oligomers, dendritic spine loss, Alzheimer's disease, RhoA/ROCK signaling, actin cytoskeleton, hippocampal neurons, synaptic loss, neurotrophin receptor signaling
MeSH terms
Alzheimer Disease, Animals, Disease Models, Animal, Hippocampus, Signal Transduction, Amyloid beta-Peptides, Receptors, Nerve Growth Factor, Mice, Knockout, Dendritic Spines, Mice

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