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The Journal of Neuroscience, July 19, 2006, 26(29):7756-7766; doi:10.1523/JNEUROSCI.1560-06.2006

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Development/Plasticity/Repair
Interaction of Survival and Death Signaling in Basal Forebrain Neurons: Roles of Neurotrophins and Proneurotrophins

Marta Volosin,^1 * Wenyu Song,^1 * Ramiro D. Almeida,² David R. Kaplan,³ Barbara L. Hempstead,² and Wilma J. Friedman¹

¹Department of Biological Sciences, Rutgers University, Newark, New Jersey 07102, ²Weill Medical College of Cornell University, New York, New York 10021, and ³Cancer Research Program, Hospital for Sick Children, and Department of Medical Genetics and Microbiology, University of Toronto, Ontario, Canada M5G 1X8

Correspondence should be addressed to Dr. Wilma J. Friedman, Department of Biological Sciences, Rutgers University, 101 Warren Street, Newark, NJ 07102. Email: wilmaf{at}andromeda.rutgers.edu

Proneurotrophins bind with high affinity to p75 neurotrophin receptor (p75^NTR) and lack the capacity to bind Trk receptors, suggesting that proneurotrophins can elicit apoptosis via p75^NTR even in cells expressing survival-promoting Trk receptors. In the CNS, basal forebrain (BF) neurons are particularly vulnerable to degeneration in Alzheimer’s disease, and are among the few populations of brain neurons that express p75^NTR throughout life. These neurons also express Trk receptors and may be concomitantly exposed to both proneurotrophins and mature neurotrophins during development, disease, or after injury. We investigated the interaction of mature and proneurotrophin signaling in these CNS neurons. Kainic acid-induced seizures elicited production of pro-NGF by BF astrocytes before caspase activation in p75^NTR-positive BF neurons, demonstrating local production of proneurotrophins under pathological conditions and suggesting apoptotic signaling in vivo. Mechanisms of proneurotrophin-induced death were analyzed in cultured BF neurons, and required both p75^NTR and its coreceptor sortilin. Surprisingly, exposure to both mature neurotrophins and proneurotrophins demonstrated that Trk phosphorylation did not prevent pro-NGF-induced apoptosis via p75^NTR. However, activation of PI3K (phosphatidylinositol 3-kinase)/Akt and MEK (mitogen-activated protein kinase kinase)/Erk pathways prevented pro-NGF-induced apoptosis, revealing a novel critical checkpoint in survival versus apoptotic signaling downstream of Trk activation, and suggesting that pro-NGF blocks survival signaling by preventing Akt and Erk activation. This study shows that proneurotrophins are produced in the brain under pathological conditions, and can elicit apoptosis of BF neurons even when Trk receptors are activated.

Key words: neurotrophins; p75 neurotrophin receptor; apoptosis; signal transduction; basal forebrain; Trk

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Received Nov. 23, 2005; revised June 8, 2006; accepted June 10, 2006.

Correspondence should be addressed to Dr. Wilma J. Friedman, Department of Biological Sciences, Rutgers University, 101 Warren Street, Newark, NJ 07102. Email: wilmaf{at}andromeda.rutgers.edu

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