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The Journal of Neuroscience, August 13, 2003, 23(19):7385-7394

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p75 Neurotrophin Receptor Protects Primary Cultures of Human Neurons against Extracellular Amyloid Peptide Cytotoxicity

Yan Zhang,^2,4 Yanguo Hong,⁴ Younes Bounhar,^2,4 Megan Blacker,⁴ Xavier Roucou,⁴ Omar Tounekti,⁴ Emily Vereker,⁴ William J. Bowers,¹ Howard J. Federoff,¹ Cynthia G. Goodyer,³ and Andréa LeBlanc^2,4

¹Department of Neurology and Center for Aging and Developmental Biology, University of Rochester, Rochester, New York 14642, Departments of ²Neurology and Neurosurgery and ³Pediatrics, McGill University, Montreal, Quebec, Canada H3A 2B4, and ⁴Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada H3T 1E2

The cytotoxicity of extracellular amyloid peptide (A) has been clearly demonstrated in many cell types. In contrast, primary human neurons in culture are resistant to extracellular A-mediated toxicity. Here, we investigate the involvement of p75 neurotrophin receptor (p75^NTR) in A-treated human neurons. We find that A_1-40 and A_1-42, but not the reverse control peptide, A_40-1, rapidly increase the levels of p75^NTR in a specific and dose-dependent manner. In contrast to observations in cell lines, enhanced expression of p75^NTR in human neurons via a herpes simplex virus amplicon vector does not increase the susceptibility of neurons to A. Unexpectedly, inhibition of p75^NTR expression with an antisense expression construct or incubation of the cells with an antibody to the extracellular domain of p75^NTR sensitizes human neurons to extracellular nonfibrillar or fibrillar A_1-42 cytotoxicity. Unlike intracellular A, extracellular A toxicity is independent of p53 and Bax activity. However, A toxicity is inhibited by caspase inhibitors and the glycogen synthase kinase 3 inhibitor lithium. Neuroprotection against A is phosphatidylinositide 3-kinase dependent but Akt independent. These results are consistent with a neuroprotective role for p75^NTR against extracellular A toxicity in human neurons.

Key words: Alzheimer; primary human neurons; p75 neurotrophin receptor; amyloid peptide; neurotoxicity; neuroprotection

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Received Apr. 2, 2003; revised Jun. 16, 2003; accepted Jun. 18, 2003.

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