ProNGF, but Not NGF, Switches from Neurotrophic to Apoptotic Activity in Response to Reductions in TrkA Receptor Levels

Ioannou, Maria S.; Fahnestock, Margaret

doi:10.3390/ijms18030599

Cited by 77 publications

(78 citation statements)

References 49 publications

(78 reference statements)

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“…In p75KO, improved ratio of NGF to proNGF was paralleled with restoration of the TrkA phosphorylation in diabetic retina compared to controls. This observation is critical in the light of recent findings that proNGF can switch between neurotropic and apoptotic activity in response to changes in TrkA receptor levels [31]. Our results lend further support to the interplay between p75 NTR expression and TrkA activation previously demonstrated in retinal endothelial cells [17,32] and in hypoxia-induced retinal neovascularization model [33].…”

Section: Resultssupporting

confidence: 88%

Deletion of the Neurotrophin Receptor p75NTR Prevents Diabetes-Induced Retinal Acellular Capillaries in Streptozotocin-Induced Mouse Diabetic Model

Mohamed

Shanab

Remessy

2016

JDMDC

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Diabetic retinopathy is characterized by early stage of retinal neuro-inflammation that triggers development of acellular capillaries and a late stage of pathological neovascularization. Due to limited treatment options, there is a pressing need to develop new therapeutics. Our group discovered that diabetes-impaired processing of the nerve growth factor precursor (proNGF) resulting in its accumulation and its receptor p75NTR. Here, we examine the protective effects of modulating p75NTR in experimental model of diabetic retinopathy. Diabetes was induced using streptozotocin in both wild type (WT) and p75NTR knockout (p75KO) mice. Retinal inflammation and microvascular dysfunction were assessed. Western blot analysis was performed to assess expression of apoptotic and inflammatory markers and levels of the neurotrophin, p75NTR and ephrin-B2. Deletion of p75NTR did not alter body weight or diabetes status compared to WT mice. In WT-mice, diabetes triggered retinal inflammation, significant decrease in pericyte count and marked increase in development of occluded (acellular) capillary formation after 24-weeks. Deletion of p75NTR prevented acellular capillary, restored pericyte count, and inhibited the retinal Ephrin-B2, activation of the stress-kinase JNK and apoptotic marker cleaved caspase-3 in the diabetic retina. Deletion of p75NTR reduced retinal inflammation, and proNGF expression. These effects coincided with increased NGF level and TrkA activation in the diabetic retina. Targeting p75NTR using genetic approach protected the retina from the impact of long-term diabetes in mediating microvascular degeneration and maintains the balance of NGF/proNGF level. Together, these results provide rationale that targeting p75NTR may offer novel and effective therapeutic strategy to combat diabetic retinopathy.

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Section: Resultssupporting

confidence: 88%

Deletion of the Neurotrophin Receptor p75NTR Prevents Diabetes-Induced Retinal Acellular Capillaries in Streptozotocin-Induced Mouse Diabetic Model

Mohamed

Shanab

Remessy

2016

JDMDC

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Section: Discussionmentioning

confidence: 71%

“…The observed preferential decrease in TrkA receptor expression in cholinergic neurons after diabetes induction could shift the activity of the proNGF/mNGF system toward that elicited by the challenge of the p75 NTR . Supporting this hypothesis, previous data indicates that the prosurvival versus the proapoptotic activity of proNGF is strictly dependent upon the relative amount of the two receptors expressed by responsive cells (Ioannou & Fahnestock, ; Masoudi et al, ). Therefore, our data suggest that in diabetic rat brains, cholinergic cells selectively down‐regulate the NGF‐receptor type that stimulates ChAT gene expression (Pongrac & Rylett, ), while maintaining the responsivity to proNGF through p75 NTR unaltered.…”

Section: Discussionmentioning

confidence: 77%

Electroacupuncture in rats normalizes the diabetes‐induced alterations in the septo‐hippocampal cholinergic system

Protto

Soligo

Stefano³

et al. 2019

Hippocampus

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Diabetes induces early sufferance in the cholinergic septo‐hippocampal system, characterized by deficits in learning and memory, reduced hippocampal plasticity and abnormal pro‐nerve growth factor (proNGF) release from hippocampal cells, all linked to dysfunctions in the muscarinic cholinergic modulation of hippocampal physiology. These alterations are associated with dysregulation of several cholinergic markers, such as the NGF receptor system and the acetylcholine biosynthetic enzyme choline‐acetyl transferase (ChAT), in the medial septum and its target, the hippocampus. Controlled and repeated sensory stimulation by electroacupuncture has been proven effective in counteracting the consequences of diabetes on cholinergic system physiology in the brain. Here, we used a well‐established Type 1 diabetes model, obtained by injecting young adult male rats with streptozotocin, to induce sufferance in the septo‐hippocampal system. We then evaluated the effects of a 3‐week treatment with low‐frequency electroacupuncture on: (a) the expression and protein distribution of proNGF in the hippocampus, (b) the tissue distribution and content of NGF receptors in the medial septum, (c) the neuronal cholinergic and glial phenotype in the septo‐hippocampal circuitry. Twice‐a‐week treatment with low‐frequency electroacupuncture normalized, in both hippocampus and medial septum, the ratio between the neurotrophic NGF and its neurotoxic counterpart, the precursor proNGF. Electroacupuncture regulated the balance between the two major proNGF variants (proNGF‐A and proNGF‐B) at both gene expression and protein synthesis levels. In addition, electroacupuncture recovered to basal level the pro‐neurotrophic NGF receptor tropomyosin receptor kinase‐A content, down‐regulated in medial septum cholinergic neurons by diabetes. Electroacupuncture also regulated ChAT content in medial septum neurons and its anterograde transport toward the hippocampus. Our data indicate that repeated sensory stimulation can positively affect brain circuits involved in learning and memory, reverting early impairment induced by diabetes development. Electroacupuncture could exert its effects on the septo‐hippocampal cholinergic neurotransmission in diabetic rats, not only by rescuing the hippocampal muscarinic responsivity, as previously described, but also normalizing acetylcholine biosynthesis and NGF metabolism in the hippocampus.

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“…P75NTR is a common receptor for all neurotrophins, that partners with tyrosine kinase (TrK) receptors to regulate stem cell differentiation, apoptosis, migration and several other biological processes [34,35]. p75NTR is particularly enriched in neural crest stem cells [36], and in neurosphere forming NPCs of diverse origin [37,38,39], whereby it is a bona-fide NSC/NPC marker.…”

Section: Discussionmentioning

confidence: 99%

Structure and ultrastructure of neurospheres spontaneously generated in culture from sheep ovarian cortical cells.

Salvador¹,

Maldonado²,

Galicia³

et al. 2019

Preprint

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Background: Neurospheres derived from adult stem cells of non-neural tissues represent a promising source of neural stem cells (NSCs) and neural progenitor cells (NPCs) for autologous cell therapy in neurological diseases. Analyzing the fine structure of neurospheres can provide pivotal information regarding the phenotype of spheroid-integrating cells, being useful for cell characterization during differentiation, and oncogenic transformation. Neurospheres can be generated by culturing ovarian cortical cells under particular conditions. In order to assess the reliability of use of these spheroids in regenerative medicine, developmental biology, and to state whether they share morphological features with central nervous system (CNS) derived neurospheres, they were analyzed by light and transmission electron microscopy. Sheep ovarian cortical cells were cultured in serum-free medium for 21 days to generate neurospheres. On days 10, 15 and 21 of culture, expression of pluripotency (Nanog, Oct4, Sox2), and NSC/NPC (nestin, Pax6, P75NTR) transcripts by qRT-PCR, immunolocalization of NSC/NPC antigens (nestin, Pax6, P75NTR), structure, and ultrastructure, were analyzed in spheroids. Results: Spheroids expressed transcripts and antigens of pluripotency, and NSC/NPC. Structural analyses revealed that cells were arranged in a peripheral sheet cover comprised by a few layers of spindle-shaped cells exhibiting frequent mitoses, and large round cells; and an inner core, with intermediate-sized cells showing frequent events of apoptosis and necrosis. Ultrastructural analyses showed that in the inner core, most cells were electron dense (dark), showing frequent apoptotic and degenerative events; the outer epithelium-like sheet, was formed by low electron dense cells (light flat cells; LFCs) showing signs of intense metabolic activity, abundant cytoplasmic organelles, phagosomes, lysosome-like structures, apical microvilli, and filament bundles of cytoskeleton elements, indicating that LFCs play a role in extracellular exchanges. Apical-basal polarization of LFCs evidenced by frequent intercellular contacts, like adherens junctions and cytoplasmic interdigitations, was lost in some cells whose contacts with neighboring cells were loose intedigitations and expanded cytoplasmic processes. This might anticipate disengaging/aggregating of light protruding cells (LPCs) from/to the neurosphere, as consistently observed in cultures by inverted microscopy. Conclusions: Neurospheres spontaneously generated from ovarian cortical cells in culture, share most structural and ultrastructural characteristics of neurospheres derived from the CNS.

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ProNGF, but Not NGF, Switches from Neurotrophic to Apoptotic Activity in Response to Reductions in TrkA Receptor Levels

Cited by 77 publications

References 49 publications

Deletion of the Neurotrophin Receptor p75NTR Prevents Diabetes-Induced Retinal Acellular Capillaries in Streptozotocin-Induced Mouse Diabetic Model

Deletion of the Neurotrophin Receptor p75NTR Prevents Diabetes-Induced Retinal Acellular Capillaries in Streptozotocin-Induced Mouse Diabetic Model

Electroacupuncture in rats normalizes the diabetes‐induced alterations in the septo‐hippocampal cholinergic system

Structure and ultrastructure of neurospheres spontaneously generated in culture from sheep ovarian cortical cells.

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