Nerve Growth Factor in Neurodevelopmental and Neurodegenerative Diseases

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 21972

Special Issue Editor

1. Institute of Physiology, Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, 44121 Ferrara, Italy
2. Bio@SNS Laboratory, Scuola Normale Superiore, Piazza dei Cavalieri 7, 56126 Pisa, Italy
Interests: nerve growth factor (NGF); neurodevelopmental and neurodegenerative diseases; congenital neuropathies; glia physiology
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Special Issue Information

Dear Colleagues,

It is well established that the neurotrophin nerve growth factor (NGF) plays an important role in the survival, maintenance, and differentiation of sensory and sympathetic neurons and in specific neuronal populations in the adult brain. More recently, it has been demonstrated that the NGF system is much more complex, since its precursor molecule pro-NGF is also endowed with biological activity. In addition, attention has been given to the fact that NGF receptors are more widely distributed, being expressed not only in neuronal populations but also in the immune system and brain glial cells. Bearing in mind these findings, a disequilibrium in NGF or pro-NGF expression, as well as changes in the types of receptor available and in their respective levels of expression, may play multiple roles in the development and progression of many diseases. Consequently, NGF can be considered a potential therapeutic for several neurodevelopmental and neurodegenerative diseases. However, a therapy involving NGF protein in the brain has inherent problems because of the inability to cross the blood–brain barrier and its pro-nociceptive activity. In this Special Issue of Cells, we are inviting contributions either in the form of original research articles, reviews, or shorter perspective articles on all aspects related to the subject of “NGF in Neurodevelopmental and Neurodegenerative Diseases”.

Prof. Dr. Simona Capsoni
Guest Editor

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Keywords

  • Nerve growth factor cell targets
  • Pro-NGF
  • TrkA
  • P75NTR
  • NGF intracellular signaling
  • Microglia
  • Astrocytes
  • Inflammation
  • Neurogenesis
  • Therapeutic use
  • Delivery strategy

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Published Papers (7 papers)

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Research

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16 pages, 5264 KiB  
Article
Computational Insights into the Sequence-Activity Relationships of the NGF(1–14) Peptide by Molecular Dynamics Simulations
by Serena Vittorio, Candida Manelfi, Silvia Gervasoni, Andrea R. Beccari, Alessandro Pedretti, Giulio Vistoli and Carmine Talarico
Cells 2022, 11(18), 2808; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11182808 - 08 Sep 2022
Cited by 2 | Viewed by 1344
Abstract
The Nerve Growth Factor (NGF) belongs to the neurothrophins protein family involved in the survival of neurons in the nervous system. The interaction of NGF with its high-affinity receptor TrkA mediates different cellular pathways related to Alzheimer’s disease, pain, ocular dysfunction, and cancer. [...] Read more.
The Nerve Growth Factor (NGF) belongs to the neurothrophins protein family involved in the survival of neurons in the nervous system. The interaction of NGF with its high-affinity receptor TrkA mediates different cellular pathways related to Alzheimer’s disease, pain, ocular dysfunction, and cancer. Therefore, targeting NGF-TrkA interaction represents a valuable strategy for the development of new therapeutic agents. In recent years, experimental studies have revealed that peptides belonging to the N-terminal domain of NGF are able to partly mimic the biological activity of the whole protein paving the way towards the development of small peptides that can selectively target specific signaling pathways. Hence, understanding the molecular basis of the interaction between the N-terminal segment of NGF and TrkA is fundamental for the rational design of new peptides mimicking the NGF N-terminal domain. In this study, molecular dynamics simulation, binding free energy calculations and per-residue energy decomposition analysis were combined in order to explore the molecular recognition pattern between the experimentally active NGF(1–14) peptide and TrkA. The results highlighted the importance of His4, Arg9 and Glu11 as crucial residues for the stabilization of NGF(1–14)-TrkA interaction, thus suggesting useful insights for the structure-based design of new therapeutic peptides able to modulate NGF-TrkA interaction. Full article
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21 pages, 6855 KiB  
Article
Amyloid-Beta Peptides and Activated Astroglia Impairs Proliferation of Nerve Growth Factor Releasing Cells In Vitro: Implication for Encapsulated Cell Biodelivery-Mediated AD Therapy
by Sumonto Mitra, Silvia Turchetto, Winant Van Os, Lars U. Wahlberg, Bengt Linderoth, Homira Behbahani and Maria Eriksdotter
Cells 2021, 10(11), 2834; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10112834 - 21 Oct 2021
Cited by 2 | Viewed by 2519
Abstract
Alzheimer’s disease (AD) treatment is constrained due to the inability of peripherally administered therapeutic molecules to cross the blood–brain barrier. Encapsulated cell biodelivery (ECB) devices, a tissue-targeted approach for local drug release, was previously optimized for human mature nerve growth factor (hmNGF) delivery [...] Read more.
Alzheimer’s disease (AD) treatment is constrained due to the inability of peripherally administered therapeutic molecules to cross the blood–brain barrier. Encapsulated cell biodelivery (ECB) devices, a tissue-targeted approach for local drug release, was previously optimized for human mature nerve growth factor (hmNGF) delivery in AD patients but was found to have reduced hmNGF release over time. To understand the reason behind reduced ECB efficacy, we exposed hmNGF-releasing cells (NGC0211) in vitro to human cerebrospinal fluid (CSF) obtained from Subjective Cognitive Impairment (SCI), Lewy Body Dementia (LBD), and AD patients. Subsequently, we exposed NGC0211 cells directly to AD-related factors like amyloid-β peptides (Aβ40/42) or activated astrocyte-conditioned medium (Aβ40/42/IL-1β/TNFα-treated) and evaluated biochemical stress markers, cell death indicators, cell proliferation marker (Ki67), and hmNGF release. We found that all patients’ CSF significantly reduced hmNGF release from NGC0211 cells in vitro. Aβ40/42, inflammatory molecules, and activated astrocytes significantly affected NGC0211 cell proliferation without altering hmNGF release or other parameters important for essential functions of the NGC0211 cells. Long-term constant cell proliferation within the ECB device is critically important to maintain a steady cell population needed for stable mNGF release. These data show hampered proliferation of NGC0211 cells, which may lead to a decline of the NGC0211 cell population in ECBs, thereby reducing hmNGF release. Our study highlights the need for future studies to strengthen ECB-mediated long-term drug delivery approaches. Full article
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23 pages, 2609 KiB  
Article
Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction
by Märta Dahlström, Nather Madjid, Gunnar Nordvall, Magnus M. Halldin, Erika Vazquez-Juarez, Maria Lindskog, Johan Sandin, Bengt Winblad, Maria Eriksdotter and Pontus Forsell
Cells 2021, 10(8), 1871; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10081871 - 23 Jul 2021
Cited by 11 | Viewed by 4734
Abstract
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and results in severe neurodegeneration and progressive cognitive decline. Neurotrophins are growth factors involved in the development and survival of neurons, but also in underlying mechanisms for memory formation such as hippocampal long-term potentiation. [...] Read more.
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and results in severe neurodegeneration and progressive cognitive decline. Neurotrophins are growth factors involved in the development and survival of neurons, but also in underlying mechanisms for memory formation such as hippocampal long-term potentiation. Our aim was to identify small molecules with stimulatory effects on the signaling of two neurotrophins, the nerve growth factor (NGF) and the brain derived neurotrophic factor (BDNF). To identify molecules that could potentiate neurotrophin signaling, 25,000 molecules were screened, which led to the identification of the triazinetrione derivatives ACD855 (Ponazuril) and later on ACD856, as positive allosteric modulators of tropomyosin related kinase (Trk) receptors. ACD855 or ACD856 potentiated the cellular signaling of the neurotrophin receptors with EC50 values of 1.9 and 3.2 or 0.38 and 0.30 µM, respectively, for TrkA or TrkB. ACD855 increased acetylcholine levels in the hippocampus by 40% and facilitated long term potentiation in rat brain slices. The compounds acted as cognitive enhancers in a TrkB-dependent manner in several different behavioral models. Finally, the age-induced cognitive dysfunction in 18-month-old mice could be restored to the same level as found in 2-month-old mice after a single treatment of ACD856. We have identified a novel mechanism to modulate the activity of the Trk-receptors. The identification of the positive allosteric modulators of the Trk-receptors might have implications for the treatment of Alzheimer’s diseases and other diseases characterized by cognitive impairment. Full article
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Review

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15 pages, 901 KiB  
Review
A Microglial Function for the Nerve Growth Factor: Predictions of the Unpredictable
by Alexia Tiberi, Simona Capsoni and Antonino Cattaneo
Cells 2022, 11(11), 1835; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11111835 - 03 Jun 2022
Cited by 3 | Viewed by 2512
Abstract
Microglia are the only immune cell population present in the brain parenchyma. Their vantage position in the central nervous system (CNS) enables these myeloid cells to perform the most disparate of tasks: from the classical immune functions of fighting infections and surveilling the [...] Read more.
Microglia are the only immune cell population present in the brain parenchyma. Their vantage position in the central nervous system (CNS) enables these myeloid cells to perform the most disparate of tasks: from the classical immune functions of fighting infections and surveilling the extracellular space for pathogens and damage, to sculpting the neuronal circuitry by pruning unnecessary synapses and assisting neurons in spine formation, aiding in the maintenance of brain homeostasis. The neurotrophin field has always been dominated by the neurocentric view that the primary target of these molecules must be neurons: this holds true even for the Nerve Growth Factor (NGF), which owes its popularity in the neuroscience community to its trophic and tropic activity towards sensory and sympathetic neurons in the peripheral nervous system, and cholinergic neurons in the CNS. The increasing evidence that microglia are an integral part of neuronal computation calls for a closer look as to whether these glial cells are capable of responding directly to NGF. In this review, we will first outline evidence in support of a role for NGF as a molecule mediating neuroimmune communication. Then, we will illustrate some of those non-immune features that have made microglial cells one of the hottest topics of this last decade. In conclusion, we will discuss evidence in support of a microglial function for NGF. Full article
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15 pages, 1005 KiB  
Review
The Nerve Growth Factor Metabolic Pathway Dysregulation as Cause of Alzheimer’s Cholinergic Atrophy
by Sonia Do Carmo, Benjamin Kannel and A. Claudio Cuello
Cells 2022, 11(1), 16; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11010016 - 22 Dec 2021
Cited by 12 | Viewed by 3807
Abstract
The cause of the loss of basal forebrain cholinergic neurons (BFCNs) and their terminal synapses in the cerebral cortex and hippocampus in Alzheimer’s disease (AD) has provoked a decades-long controversy. The cholinergic phenotype of this neuronal system, involved in numerous cognitive mechanisms, is [...] Read more.
The cause of the loss of basal forebrain cholinergic neurons (BFCNs) and their terminal synapses in the cerebral cortex and hippocampus in Alzheimer’s disease (AD) has provoked a decades-long controversy. The cholinergic phenotype of this neuronal system, involved in numerous cognitive mechanisms, is tightly dependent on the target-derived nerve growth factor (NGF). Consequently, the loss of BFCNs cholinergic phenotype in AD was initially suspected to be due to an NGF trophic failure. However, in AD there is a normal NGF synthesis and abundance of the NGF precursor (proNGF), therefore the NGF trophic failure hypothesis for the atrophy of BCNs was abandoned. In this review, we discuss the history of NGF-dependency of BFCNs and the atrophy of these neurons in Alzheimer’s disease (AD). Further to it, we propose that trophic factor failure explains the BFCNs atrophy in AD. We discuss evidence of the occurrence of a brain NGF metabolic pathway, the dysregulation of which, in AD explains the severe deficiency of NGF trophic support for the maintenance of BFCNs cholinergic phenotype. Finally, we revise recent evidence that the NGF metabolic dysregulation in AD pathology starts at preclinical stages. We also propose that the alteration of NGF metabolism-related markers in body fluids might assist in the AD preclinical diagnosis. Full article
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17 pages, 5049 KiB  
Review
Small Endogenous Ligands Modulation of Nerve Growth Factor Bioactivity: A Structural Biology Overview
by Francesca Paoletti and Doriano Lamba
Cells 2021, 10(12), 3462; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10123462 - 08 Dec 2021
Cited by 3 | Viewed by 2247
Abstract
Experiments with cell cultures and animal models have provided solid support for the assumption that Nerve Growth Factor (NGF) plays a key role in the regulation of neuronal cell survival and death. Recently, endogenous ligands have been proposed as physiological modulators of NGF [...] Read more.
Experiments with cell cultures and animal models have provided solid support for the assumption that Nerve Growth Factor (NGF) plays a key role in the regulation of neuronal cell survival and death. Recently, endogenous ligands have been proposed as physiological modulators of NGF biological activity as part of this regulatory cascade. However, the structural and mechanistic determinants for NGF bioactivity remain to be elucidated. We recently unveiled, by an integrated structural biology approach, the ATP binding sites of NGF and investigated the effects on TrkA and p75NTR receptors binding. These results pinpoint ATP as a genuine endogenous modulator of NGF signaling, paving the way to the characterization of not-yet-identified chemical diverse endogenous biological active small molecules as novel modulators of NGF. The present review aims at providing an overview of the currently available 3D structures of NGF in complex with different small endogenous ligands, featuring the molecular footprints of the small molecules binding. This knowledge is essential for further understanding the functional role of small endogenous ligands in the modulation of neurotrophins signaling in physiological and pathological conditions and for better exploiting the therapeutic potentialities of NGF. Full article
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15 pages, 1352 KiB  
Review
Effects of Reactive Oxygen and Nitrogen Species on TrkA Expression and Signalling: Implications for proNGF in Aging and Alzheimer’s Disease
by Erika Kropf and Margaret Fahnestock
Cells 2021, 10(8), 1983; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10081983 - 04 Aug 2021
Cited by 14 | Viewed by 3754
Abstract
Nerve growth factor (NGF) and its precursor form, proNGF, are critical for neuronal survival and cognitive function. In the brain, proNGF is the only detectable form of NGF. Dysregulation of proNGF in the brain is implicated in age-related memory loss and Alzheimer’s disease [...] Read more.
Nerve growth factor (NGF) and its precursor form, proNGF, are critical for neuronal survival and cognitive function. In the brain, proNGF is the only detectable form of NGF. Dysregulation of proNGF in the brain is implicated in age-related memory loss and Alzheimer’s disease (AD). AD is characterized by early and progressive degeneration of the basal forebrain, an area critical for learning, memory, and attention. Learning and memory deficits in AD are associated with loss of proNGF survival signalling and impaired retrograde transport of proNGF to the basal forebrain. ProNGF transport and signalling may be impaired by the increased reactive oxygen and nitrogen species (ROS/RNS) observed in the aged and AD brain. The current literature suggests that ROS/RNS nitrate proNGF and reduce the expression of the proNGF receptor tropomyosin-related kinase A (TrkA), disrupting its downstream survival signalling. ROS/RNS-induced reductions in TrkA expression reduce cell viability, as proNGF loses its neurotrophic function in the absence of TrkA and instead generates apoptotic signalling via the pan-neurotrophin receptor p75NTR. ROS/RNS also interfere with kinesin and dynein motor functions, causing transport deficits. ROS/RNS-induced deficits in microtubule motor function and TrkA expression and signalling may contribute to the vulnerability of the basal forebrain in AD. Antioxidant treatments may be beneficial in restoring proNGF signalling and axonal transport and reducing basal forebrain neurodegeneration and related deficits in cognitive function. Full article
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