β-amyloid1-42 induces neuronal death through the p75 neurotrophin receptor

Sotthibundhu, Areechun, Sykes, Alex M., Fox, Briony, Underwood, Clare K., Thangnipon, Wipawan and Coulson, Elizabeth, J. (2008) β-amyloid1-42 induces neuronal death through the p75 neurotrophin receptor. The Journal of Neuroscience, 28 15: 3941-3946. doi:10.1523/JNEUROSCI.0350-08.2008

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Author Sotthibundhu, Areechun
Sykes, Alex M.
Fox, Briony
Underwood, Clare K.
Thangnipon, Wipawan
Coulson, Elizabeth, J.
Title β-amyloid1-42 induces neuronal death through the p75 neurotrophin receptor
Formatted title
β-Amyloid ₁₋₄₂ induces neuronal death through the p75 neurotrophin receptor
Journal name The Journal of Neuroscience   Check publisher's open access policy
ISSN 0270-6474
1529-2401
Publication date 2008-04-08
Year available 2008
Sub-type Article (original research)
DOI 10.1523/JNEUROSCI.0350-08.2008
Open Access Status File (Publisher version)
Volume 28
Issue 15
Start page 3941
End page 3946
Total pages 6
Editor D. C. Van Essen
Place of publication Washington, DC, United States
Publisher Society for Neuroscience
Collection year 2009
Language eng
Subject C1
110902 Cellular Nervous System
060103 Cell Development, Proliferation and Death
110904 Neurology and Neuromuscular Diseases
730104 Nervous system and disorders
Formatted abstract
Alzheimer's disease is characterized by the accumulation of neurotoxic amyloidogenic peptide Aβ, degeneration of the cholinergic innervation to the hippocampus (the septohippocampal pathway), and progressive impairment of cognitive function, particularly memory. Aβ is a ligand for the p75 neurotrophin receptor (p75NTR), which is best known for mediating neuronal death and has been consistently linked to the pathology of Alzheimer's disease. Here we examined whether p75NTR is required for Aβ-mediated effects. Treatment of wild-type but not p75NTR-deficient embryonic mouse hippocampal neurons with human Aβ1–42 peptide induced significant cell death. Furthermore, injection of Aβ1–42 into the hippocampus of adult mice resulted in significant degeneration of wild-type but not p75NTR-deficient cholinergic basal forebrain neurons, indicating that the latter are resistant to Aβ-induced toxicity. We also found that neuronal death correlated with Aβ1–42 peptide-stimulated accumulation of the death-inducing p75NTR C-terminal fragment generated by extracellular metalloprotease cleavage of full-length p75NTR. Although neuronal death was prevented in the presence of the metalloprotease inhibitor TAPI-2 (tumor necrosis factor-{alpha} protease inhibitor-2), Aβ1–42-induced accumulation of the C-terminal fragment resulted from inhibition of {gamma}-secretase activity. These results provide a novel mechanism to explain the early and characteristic loss of cholinergic neurons in the septohippocampal pathway that occurs in Alzheimer's disease.
Keyword p75NTR
Alzheimer's disease
basal forebrain
cholinergic neurons
regulated intramembrane proteolysis (RIP)
apoptosis
neurodegeneration
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2009 Higher Education Research Data Collection
Queensland Brain Institute Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 114 times in Thomson Reuters Web of Science Article | Citations
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Created: Sat, 21 Mar 2009, 01:22:47 EST by Debra McMurtrie on behalf of Queensland Brain Institute