Cited by 184Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

The p75 Neurotrophin Receptor Promotes Amyloid-β(1-42)-Induced Neuritic Dystrophy In Vitro and In Vivo

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Knowles, Juliet K., Rajadas, Jayakumar, Nguyen, Thuy-Vi V., Yang, Tao, LeMieux, Melburne C., Vander Griend, Lilith, Ishikawa, Chihiro, Massa, Stephen M. +2 more·2009·The Journal of Neuroscience

Abstract

Oligomeric forms of amyloid-beta (Abeta) are thought to play a causal role in Alzheimer's disease (AD), and the p75 neurotrophin receptor (p75(NTR)) has been implicated in Abeta-induced neurodegeneration. To further define the functions of p75(NTR) in AD, we examined the interaction of oligomeric Abeta(1-42) with p75(NTR), and the effects of that interaction on neurite integrity in neuron cultures and in a chronic AD mouse model. Atomic force microscopy was used to ascertain the aggregated state of Abeta, and fluorescence resonance energy transfer analysis revealed that Abeta oligomers interact with the extracellular domain of p75(NTR). In vitro studies of Abeta-induced death in neuron cultures isolated from wild-type and p75(NTR-/-) mice, in which the p75(NTR) extracellular domain is deleted, showed reduced sensitivity of mutant cells to Abeta-induced cell death. Interestingly, Abeta-induced neuritic dystrophy and activation of c-Jun, a known mediator of Abeta-induced deleterious signaling, were completely prevented in p75(NTR-/-) neuron cultures. Thy1-hAPP(Lond/Swe) x p75(NTR-/-) mice exhibited significantly diminished hippocampal neuritic dystrophy and complete reversal of basal forebrain cholinergic neurite degeneration relative to those expressing wild-type p75(NTR). Abeta levels were not affected, suggesting that removal of p75(NTR) extracellular domain reduced the ability of excess Abeta to promote neuritic degeneration. These findings indicate that although p75(NTR) likely does not mediate all Abeta effects, it does play a significant role in enabling Abeta-induced neurodegeneration in vitro and in vivo, establishing p75(NTR) as an important therapeutic target for AD.

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Crossref · 10.1523/jneurosci.0620-09.2009

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  • Other putative receptors/co-receptors involved in neuronal binding of Aβ oligomers include the p75 neurotrophin receptor, RAGE, nicotinic acetylcholine receptors and Frizzled.

    “Other putative receptors/co-receptors involved in neuronal binding of Aβ oligomers include the p75 neurotrophin receptor (p75NTR) (Knowles et al., 2009), the receptor for advanced glycation end products (RAGE) (Sturchler et al., 2008), nicotinic acetylcholine receptors (Magdesian et al., 2005) and Frizzled (Magdesian et al., 2008).”

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Authors
Knowles, J. K., Rajadas, J., Nguyen, T.-V. V., Yang, T., LeMieux, M. C., Vander Griend, L., Ishikawa, C., Massa, S. M., Wyss-Coray, T., & Longo, F. M.
Affiliations
  • Stanford University (US)
  • University of North Carolina at Chapel Hill (US)
  • VA Palo Alto Health Care System (US)
  • San Francisco VA Medical Center (US)
Corresponding author
Longo, Frank M.
Venue
The Journal of Neuroscience
Published
2009-08-26
Volume
29
Issue
34
Pages
10627-10637
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
OpenAlex
W2090434536
Cited by
184
References
70
Citations by year
2026: 10 · 2025: 6 · 2024: 6 · 2023: 4 · 2022: 9 · 2021: 14 · 2020: 11 · 2019: 11 · 2018: 4 · 2017: 10 · 2016: 17 · 2015: 14 · 2014: 17 · 2013: 15 · 2012: 12
FWCI
7.73
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Alzheimer's Association
  • U.S. Public Health Service (F30 NA051971)
  • National Institute of Neurological Disorders and Stroke (F30NS051971)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
p75 neurotrophin receptor, amyloid-beta 42, Alzheimer's disease, neuritic dystrophy, amyloid-beta oligomers, c-Jun activation, cholinergic neurons, hippocampus, APP transgenic mice, therapeutic target
MeSH terms
Acetylcholinesterase, Alzheimer Disease, Analysis of Variance, Animals, Cell Survival, Cells, Cultured, Disease Models, Animal, Embryo, Mammalian, Enzyme-Linked Immunosorbent Assay, Exons, Hippocampus, Humans, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Nerve Degeneration, Neurons, Peptide Fragments, Spectrophotometry, Atomic, Amyloid beta-Peptides, Neurites, Prosencephalon, Amyloid beta-Protein Precursor, Receptor, Nerve Growth Factor, Fluorescence Resonance Energy Transfer, Mice

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