Pro-NGF Isolated from the Human Brain Affected by Alzheimer's Disease Induces Neuronal Apoptosis Mediated by p75NTR

Abstract

The pro-form of nerve growth factor (pro-NGF) has been shown to be a high affinity ligand for p75NTR and to induce apoptosis through this receptor. It has been reported that pro-NGF, rather than mature NGF, is the predominant form of this neurotrophin in human brain. In the present work we studied the potential involvement of pro-NGF purified from human brains affected by Alzheimer's disease (AD), where it is especially abundant, in the neuronal apoptosis observed in this disease. Western blot analysis of human brain tissue showed the existence of several pro-NGF forms. Some of these pro-NGF forms were significantly increased in AD brain cortex in a disease stage-dependent manner. Pro-NGF, purified by chromatography from human AD brains, induced apoptotic cell death in sympathetic neurons and in a p75NTR stably transfected cell line. Blocking p75NTR in cell culture abolished neuronal apoptosis caused by pro-NGF. p75NTR-transfected cells underwent apoptosis in the presence of pro-NGF while control wild-type cells did not. Taken together, these results indicate that pro-NGF purified from AD human brains can induce apoptosis in neuronal cell cultures through its interaction with the p75NTR receptor.

Pro-NGF secreted by astrocytes promotes motor neuron cell death

“…Since proteolytic processing is altered in many neurological disorders (Rosenberg 2002) neurotrophic factor functions may be altered to influence disease progression. For example, increased levels of proNGF have been detected in Alzheimer's disease patients (Peng et al 2004;Pedraza et al 2005), but the cellular sources were not fully identified. Whether the abnormal proNGF secretion by astrocytes is the result of decreased protease activity or a general increase in neurotrophin synthesis requires further investigation.…”

“…Recent studies have shown that proneurotrophins binding to p75 mediates cell death after injury or neurodegenerative diseases such as Alzheimer's dementia (Harrington et al 2004;Peng et al 2004;Pedraza et al 2005;Volosin et al 2006). Pro-neurotrophins are produced and then cleaved by furin and other proteases to produce the mature neurotrophin (Lee et al 2001).…”

Regulation of NGF and NT-3 protein expression in peripheral targets by sympathetic input

“…Taken together, these findings suggest that high MW NGF species are abundant in the nervous system and may have their own biological activity. Some have suggested an apoptotic role for proNGF (Lee et al 2001;Beattie et al 2002;Harrington et al 2004;Pedraza et al 2005), though proNGF also has been shown to have neurotrophic activities Reinshagen et al 2000;Fahnestock et al 2004).…”

Pro-nerve Growth Factor Induces Autocrine Stimulation of Breast Cancer Cell Invasion through Tropomyosin-related Kinase A (TrkA) and Sortilin Protein

“…Nerve growth factor (NGF), 5 the prototypical member of the neurotrophin family of polypeptides, is essential for the survival and differentiation of central and peripheral neurons, and its role in the development and regeneration of the sympathetic and sensory nervous systems has been extensively described (1). NGF binds to the tropomyosin-related kinase A (TrkA) receptor, a tyrosine kinase receptor, and to the p75 neurotrophin receptor (p75 NTR ), a member of the tumor necrosis factor receptor family, to induce its neurotrophic effects.…”

“…Importantly, proNGF can be secreted without being processed to mature NGF and can have its own biological effects (3). As more than just a source for NGF, proNGF was shown to induce neuronal death by apoptosis where mature NGF induced survival and differentiation (4,5). For inducing its proapoptotic effect on neurons, proNGF forms a trimeric complex with two plasma membrane receptors: p75 NTR and sortilin (4).…”