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The Journal of Neuroscience, April 9, 2008, 28(15):3941-3946; doi:10.1523/JNEUROSCI.0350-08.2008

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Brief Communications
β-Amyloid_1–42 Induces Neuronal Death through the p75 Neurotrophin Receptor

Areechun Sotthibundhu,^1,2 Alex M. Sykes,¹ Briony Fox,¹ Clare K. Underwood,¹ Wipawan Thangnipon,² and Elizabeth J. Coulson¹

¹Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia, and ²Neuro-Behavioural Biology Centre, Institute of Science and Technology for Research and Development, Mahidol University, Salaya 73170, Thailand

Correspondence should be addressed to Elizabeth J. Coulson, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia. Email: e.coulson{at}uq.edu.au

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 (p75^NTR), which is best known for mediating neuronal death and has been consistently linked to the pathology of Alzheimer's disease. Here we examined whether p75^NTR is required for Aβ-mediated effects. Treatment of wild-type but not p75^NTR-deficient embryonic mouse hippocampal neurons with human Aβ_1–42 peptide induced significant cell death. Furthermore, injection of Aβ_1–42 into the hippocampus of adult mice resulted in significant degeneration of wild-type but not p75^NTR-deficient cholinergic basal forebrain neurons, indicating that the latter are resistant to Aβ-induced toxicity. We also found that neuronal death correlated with Aβ_1–42 peptide-stimulated accumulation of the death-inducing p75^NTR C-terminal fragment generated by extracellular metalloprotease cleavage of full-length p75^NTR. Although neuronal death was prevented in the presence of the metalloprotease inhibitor TAPI-2 (tumor necrosis factor- protease inhibitor-2), Aβ_1–42-induced accumulation of the C-terminal fragment resulted from inhibition of -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.

Key words: p75^NTR; Alzheimer's disease; basal forebrain; cholinergic neurons; regulated intramembrane proteolysis (RIP); apoptosis; neurodegeneration

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Received May 10, 2007; revised Feb. 20, 2008; accepted March 4, 2008.

Correspondence should be addressed to Elizabeth J. Coulson, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia. Email: e.coulson{at}uq.edu.au

This article has been cited by other articles:

				C. Matrone, M. T. Ciotti, D. Mercanti, R. Marolda, and P. Calissano NGF and BDNF signaling control amyloidogenic route and A{beta} production in hippocampal neurons PNAS, September 2, 2008; 105(35): 13139 - 13144. [Abstract] [Full Text] [PDF]

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