A role for the p75 neurotrophin receptor in axonal degeneration and apoptosis induced by oxidative stress.

The p75 neurotrophin receptor (p75(NTR)) mediates the death of specific populations of neurons during the development of the nervous system or after cellular injury. The receptor has also been implicated as a contributor to neurodegeneration caused by numerous pathological conditions. Because many of these conditions are associated with increases in reactive oxygen species, we investigated whether p75(NTR) has a role in neurodegeneration in response to oxidative stress. Here we demonstrate that p75(NTR) signaling is activated by 4-hydroxynonenal (HNE), a lipid peroxidation product generated naturally during oxidative stress. Exposure of sympathetic neurons to HNE resulted in neurite degeneration and apoptosis. However, these effects were reduced markedly in neurons from p75(NTR-/-) mice. The neurodegenerative effects of HNE were not associated with production of neurotrophins and were unaffected by pretreatment with a receptor-blocking antibody, suggesting that oxidative stress activates p75(NTR) via a ligand-independent mechanism. Previous studies have established that proteolysis of p75(NTR) by the metalloprotease TNFα-converting enzyme and γ-secretase is necessary for p75(NTR)-mediated apoptotic signaling. Exposure of sympathetic neurons to HNE resulted in metalloprotease- and γ-secretase-dependent cleavage of p75(NTR). Pharmacological blockade of p75(NTR) proteolysis protected sympathetic neurons from HNE-induced neurite degeneration and apoptosis, suggesting that cleavage of p75(NTR) is necessary for oxidant-induced neurodegeneration. In vivo, p75(NTR-/-) mice exhibited resistance to axonal degeneration associated with oxidative injury following administration of the neurotoxin 6-hydroxydopamine. Together, these data suggest a novel mechanism linking oxidative stress to ligand-independent cleavage of p75(NTR), resulting in axonal fragmentation and neuronal death.

LM11a-31 Inhibits p75 Neurotrophin Receptor (p75 NTR ) Cleavage and is Neuroprotective in a Cell Culture Model of Parkinson's Disease.

The p75 Neurotrophin Receptor (p75 NTR ) is a multifunctional transmembrane protein that mediates neuronal responses to pathological conditions in specific regions of the nervous system. In many biological contexts, p75 NTR signaling is initiated through sequential cleavage of the receptor by α- and γ-secretases, which releases receptor fragments for downstream signaling. Our previous work demonstrated that proteolytic processing of p75 NTR in this manner is stimulated by oxidative stress in Lund Human Mesencephalic (LUHMES) cells, a dopaminergic neuronal cell line derived from human mesencephalic tissue. Considering the vulnerability of dopaminergic neurons in the ventral mesencephalon to oxidative stress and neurodegeneration associated with Parkinson's disease (PD), we investigated the role of this signaling cascade in neurodegeneration and explored cellular processes that govern oxidative stress-induced p75 NTR signaling. In the present study, we provide evidence that oxidative stress induces cleavage of p75 NTR by promoting c-Jun N-terminal Kinase (JNK)-dependent internalization of p75 NTR from the cell surface. This activation of p75 NTR signaling is counteracted by tropomyosin-related kinase (Trk) receptor signaling; however, oxidative stress leads to Trk receptor downregulation, thereby enhancing p75 NTR processing. Importantly, we demonstrate that this pathway can be inhibited by LM11a-31, a small molecule modulator of p75 NTR , thereby conferring protection against neurodegeneration. Treatment with LM11a-31 significantly reduced p75 NTR cleavage and neuronal death associated with oxidative stress. These findings reveal novel mechanisms underlying activation of p75 NTR in response to oxidative stress, underscore a key role for p75 NTR in dopaminergic neurodegeneration, and highlight p75 NTR as a potential therapeutic target for reducing neurodegeneration in PD.

The effects of peripheral hormone responses to exercise on adult hippocampal neurogenesis.

Over the last decade, a considerable amount of new data have revealed the beneficial effects of exercise on hippocampal neurogenesis and the maintenance or improvement of cognitive function. Investigations with animal models, as well as human studies, have yielded novel understanding of the mechanisms through which endocrine signaling can stimulate neurogenesis, as well as the effects of exercise on acute and/or chronic levels of these circulating hormones. Considering the effects of aging on the decline of specific endocrine factors that affect brain health, insights in this area of research are particularly important. In this review, we discuss how different forms of exercise influence the peripheral production of specific endocrine factors, with particular emphasis on brain-derived neurotrophic factor, growth hormone, insulin-like growth factor-1, ghrelin, estrogen, testosterone, irisin, vascular endothelial growth factor, erythropoietin, and cortisol. We also describe mechanisms through which these endocrine responses to exercise induce cellular changes that increase hippocampal neurogenesis and improve cognitive function.

Quantification of Neurite Degeneration with Enhanced Accuracy and Efficiency in an In Vitro Model of Parkinson's Disease.

Neurite degeneration is associated with early stages of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease (PD), and amyotrophic lateral sclerosis. One method that is commonly used to analyze neurite degeneration involves calculation of a Degeneration Index (DI) following utilization of the Analyze Particles tool of ImageJ to detect neurite fragments in micrographs of cultured cells. However, DI analyses are prone to several types of measurement error, can be time consuming to perform, and are limited in application. Here, we describe an improved method for performing DI analyses. Accuracy of measurements was enhanced through modification of selection criteria for detecting neurite fragments, removal of image artifacts and non-neurite materials from images, and optimization of image contrast. Such enhancements were implemented into an ImageJ macro that enables rapid and fully automated DI analysis of multiple images. The macro features operations for automated removal of cell bodies from micrographs, thus expanding the application of DI analyses to use in experiments involving dissociated cultures. We present experimental findings supporting that, compared with the conventional method, the enhanced analysis method yields measurements with increased accuracy and requires significantly less time to perform. Furthermore, we demonstrate the utility of the method to investigate neurite degeneration in a cell culture model of PD by conducting an experiment revealing the effects of c-Jun N-terminal kinase (JNK) on neurite degeneration induced by oxidative stress in human mesencephalic cells. This improved analysis method may be used to gain novel insight into factors underlying neurite degeneration and the progression of neurodegenerative disorders.

c-Jun N-terminal Kinase Mediates Ligand-independent p75NTR Signaling in Mesencephalic Cells Subjected to Oxidative Stress.

The p75 neurotrophin receptor (p75NTR) is a multifunctional protein that regulates cellular responses to pathological conditions in specific regions of the nervous system. Activation of p75NTR in certain neuronal populations induces proteolytic processing of the receptor, thereby generating p75NTR fragments that facilitate downstream signaling. Expression of p75NTR has been reported in neurons of the ventral midbrain, but p75NTR signaling mechanisms in such cells are poorly understood. Here, we used Lund Human Mesencephalic cells, a population of neuronal cells derived from the ventral mesencephalon, to evaluate the effects of oxidative stress on p75NTR signaling. Subjection of the cells to oxidative stress resulted in decreased cell-surface localization of p75NTR and intracellular accumulation of p75NTR fragments. Oxidative stress-induced p75NTR processing was reduced by pharmacological inhibition of metalloproteases or γ-secretase, but was unaltered by blockade of the ligand-binding domain of p75NTR. Furthermore, inhibition of c-Jun N-terminal Kinase (JNK) decreased p75NTR cleavage induced by oxidative damage. Altogether, these results support a mechanism of p75NTR activation in which oxidative stress stimulates JNK signaling, thereby facilitating p75NTR processing via a ligand-independent mechanism involving induction of metalloprotease and γ-secretase activity. These findings reveal a novel role for JNK in ligand-independent p75NTR signaling, and, considering the susceptibility of mesencephalic neurons to oxidative damage associated with Parkinson's disease (PD), merit further investigation into the effects of p75NTR on PD-related neurodegeneration.

Expression of MYCN in Multipotent Sympathoadrenal Progenitors Induces Proliferation and Neural Differentiation, but Is Not Sufficient for Tumorigenesis.

Neuroblastoma is a pediatric malignancy of the sympathetic ganglia and adrenal glands, hypothesized to originate from progenitors of the developing sympathetic nervous system. Amplification of the MYCN oncogene is a genetic marker of risk in this disease. Understanding the impact of oncogene expression on sympathoadrenal progenitor development may improve our knowledge of neuroblastoma initiation and progression. We isolated sympathoadrenal progenitor cells from the postnatal murine adrenal gland by sphere culture and found them to be multipotent, generating differentiated colonies of neurons, Schwann cells, and myofibroblasts. MYCN overexpression in spheres promoted commitment to the neural lineage, evidenced by an increased frequency of neuron-containing colonies. MYCN promoted proliferation of both sympathoadrenal progenitor spheres and differentiated neurons derived from these spheres, but there was also an increase in apoptosis. The proliferation, apoptosis, and neural lineage commitment induced by MYCN are tumor-like characteristics and thereby support the hypothesis that multipotent adrenal medullary progenitor cells are cells of origin for neuroblastoma. We find, however, that MYCN overexpression is not sufficient for these cells to form tumors in nude mice, suggesting that additional transforming mutations are necessary for tumorigenesis.