Mechanisms of Neurodevelopment and Neurodegeneration

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 (20 July 2022) | Viewed by 50108

Special Issue Editors

The Elton Laboratory for Molecular Neuroendocrinology, Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine, The Adams Super Center for Brain Studies and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel
Interests: ADNP; ADNP syndrome; autism; Alzheimer’s disease; drug development; microtubules; tau; schizophrenia
Special Issues, Collections and Topics in MDPI journals
Department of Basic Medical Sciences, Faculty of Health Sciences, School of Medicine, Institute of Biomedical Technologies (ITB), University of La Laguna, 38071 Tenerife, Spain
Interests: microtubules; microtubule-associated proteins (MAPs); tau protein; +TIPs; neurodegeneration; Alzheimer's disease; axon outgrowth; neurite extension

Special Issue Information

Dear Colleagues,

Neurons undergo a long and intricate trip during their lifetime. Neurodevelopment starts early in embryonic life, continues during adolescence, and finishes in young adulthood. Neuronal development involves diverse coordinated processes that converge on the establishment and maintenance of the complex neuronal morphology and the accurate formation of an elaborate network of synaptic contacts. Genetic and environmental factors play key roles in shaping the proper wiring of the brain. The impairment of neurodevelopmental processes may lead to lifelong disabilities—the so-called neurodevelopmental disorders. On the other hand, neurodegenerative disorders are mostly associated with aging. Neurodegeneration implies the progressive dysfunction and loss of neurons in specific brain regions that leads to alterations in brain connectivity and cognitive decline. Strikingly, neurodevelopment and neurodegeneration share a number of molecular and cellular mechanisms. Unravelling the mechanisms involved in neuronal development and degeneration will help us understand—and hopefully prevent and/or revert—the pathogenesis of neurodevelopmental and neurodegenerative disorders.

This Special Issue of Cells aims to provide a comprehensive overview of the latest research on the “Mechanisms of Neurodevelopment and Neurodegeneration”. Original articles, reviews, novel methods, and perspective articles on both basic and translational aspects are welcome. Suggested topics include:

  • Neurodevelopment:
    • Physiological mechanisms of: neurogenesis, neuronal migration, neuronal polarity, growth cone advance, neurite extension, axon outgrowth and guidance, dendritogenesis, and synaptogenesis;
    • Pathogenesis of neurodevelopmental disorders;
    • Diagnostics and drug development;
    • Neurodegeneration:
  • Neurodegeneration:
    • Molecular and cellular mechanisms involved in the onset of neurodegenerative disorders;
    • Diagnostics and drug development.

Prof. Illana Gozes
Dr. Carmen Laura Sayas
Guest Editors

Manuscript Submission Information

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Keywords

  • neuronal development
  • neurodegeneration
  • neurodevelopmental disorders
  • neurodegenerative diseases

Published Papers (14 papers)

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Research

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25 pages, 6858 KiB  
Article
Multiple Copies of microRNA Binding Sites in Long 3′UTR Variants Regulate Axonal Translation
by Luba Farberov, Ariel Ionescu, Yazeed Zoabi, Guy Shapira, Amjd Ibraheem, Yosi Azan, Eran Perlson and Noam Shomron
Cells 2023, 12(2), 233; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12020233 - 06 Jan 2023
Cited by 3 | Viewed by 2418
Abstract
Rapid responses to changes within subcellular compartments of highly polarized cells, such as neuron axons, depend on local translation and post-transcriptional regulation. The mechanism by which microRNAs (miRNAs) regulate this process is not fully understood. Here, using live cell imaging and RNA sequencing [...] Read more.
Rapid responses to changes within subcellular compartments of highly polarized cells, such as neuron axons, depend on local translation and post-transcriptional regulation. The mechanism by which microRNAs (miRNAs) regulate this process is not fully understood. Here, using live cell imaging and RNA sequencing analysis, we demonstrated how miRNAs can differentially control hundreds of transcripts at the subcellular level. We demonstrated that the seed match length of the miRNA target-sequence regulates both mRNA stability and protein translation rates. While longer seed matches have an increased inhibitory effect, transcriptome analysis did not reveal differences in seed match length between axonal and somata mRNAs of motor neurons. However, mRNA variants with longer 3′UTR are enriched in axons and contain multiple repeats of specific miRNA target sequences. Finally, we demonstrated that the long 3′UTR mRNA variant of the motor protein Kif5b is enriched explicitly in motor neuron axons and contains multiple sequence repeats for binding miR-129-5p. This subsequently results in the differential post-transcriptional regulation of kif5b and its synthesis in axons. Thus, we suggest that the number of miRNA binding sites at the 3′UTR of the mRNA, rather than the miRNA seed match length, regulates the axonal transcriptome. Full article
(This article belongs to the Special Issue Mechanisms of Neurodevelopment and Neurodegeneration)
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25 pages, 5793 KiB  
Article
Dual-Specificity Protein Phosphatase 4 (DUSP4) Overexpression Improves Learning Behavior Selectively in Female 5xFAD Mice, and Reduces β-Amyloid Load in Males and Females
by Allen L. Pan, Mickael Audrain, Emmy Sakakibara, Rajeev Joshi, Xiaodong Zhu, Qian Wang, Minghui Wang, Noam D. Beckmann, Eric E. Schadt, Sam Gandy, Bin Zhang, Michelle E. Ehrlich and Stephen R. Salton
Cells 2022, 11(23), 3880; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11233880 - 01 Dec 2022
Cited by 3 | Viewed by 2226
Abstract
Recent multiscale network analyses of banked brains from subjects who died of late-onset sporadic Alzheimer’s disease converged on VGF (non-acronymic) as a key hub or driver. Within this computational VGF network, we identified the dual-specificity protein phosphatase 4 (DUSP4) [also known [...] Read more.
Recent multiscale network analyses of banked brains from subjects who died of late-onset sporadic Alzheimer’s disease converged on VGF (non-acronymic) as a key hub or driver. Within this computational VGF network, we identified the dual-specificity protein phosphatase 4 (DUSP4) [also known as mitogen-activated protein kinase (MAPK) phosphatase 2] as an important node. Importantly, DUSP4 gene expression, like that of VGF, is downregulated in postmortem Alzheimer’s disease (AD) brains. We investigated the roles that this VGF/DUSP4 network plays in the development of learning behavior impairment and neuropathology in the 5xFAD amyloidopathy mouse model. We found reductions in DUSP4 expression in the hippocampi of male AD subjects, correlating with increased CDR scores, and in 4-month-old female and 12–18-month-old male 5xFAD hippocampi. Adeno-associated virus (AAV5)-mediated overexpression of DUSP4 in 5xFAD mouse dorsal hippocampi (dHc) rescued impaired Barnes maze performance in females but not in males, while amyloid loads were reduced in both females and males. Bulk RNA sequencing of the dHc from 5-month-old mice overexpressing DUSP4, and Ingenuity Pathway and Enrichr analyses of differentially expressed genes (DEGs), revealed that DUSP4 reduced gene expression in female 5xFAD mice in neuroinflammatory, interferon-gamma (IFNγ), programmed cell death protein-ligand 1/programmed cell death protein 1 (PD-L1/PD-1), and extracellular signal-regulated kinase (ERK)/MAPK pathways, via which DUSP4 may modulate AD phenotype with gender-specificity. Full article
(This article belongs to the Special Issue Mechanisms of Neurodevelopment and Neurodegeneration)
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14 pages, 3803 KiB  
Article
Distinct Impairments Characterizing Different ADNP Mutants Reveal Aberrant Cytoplasmic-Nuclear Crosstalk
by Maram Ganaiem, Gidon Karmon, Yanina Ivashko-Pachima and Illana Gozes
Cells 2022, 11(19), 2994; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11192994 - 26 Sep 2022
Cited by 7 | Viewed by 3153
Abstract
(1) Background: Activity-dependent neuroprotective protein (ADNP) is essential for neuronal structure and function. Multiple de novo pathological mutations in ADNP cause the autistic ADNP syndrome, and they have been further suggested to affect Alzheimer’s disease progression in a somatic form. Here, we asked [...] Read more.
(1) Background: Activity-dependent neuroprotective protein (ADNP) is essential for neuronal structure and function. Multiple de novo pathological mutations in ADNP cause the autistic ADNP syndrome, and they have been further suggested to affect Alzheimer’s disease progression in a somatic form. Here, we asked if different ADNP mutations produce specific neuronal-like phenotypes toward better understanding and personalized medicine. (2) Methods: We employed CRISPR/Cas9 genome editing in N1E-115 neuroblastoma cells to form neuron-like cell lines expressing ADNP mutant proteins conjugated to GFP. These new cell lines were characterized by quantitative morphology, immunocytochemistry and live cell imaging. (3) Results: Our novel cell lines, constitutively expressing GFP-ADNP p.Pro403 (p.Ser404* human orthologue) and GFP-ADNP p.Tyr718* (p.Tyr719* human orthologue), revealed new and distinct phenotypes. Increased neurite numbers (day 1, in culture) and increased neurite lengths upon differentiation (day 7, in culture) were linked with p.Pro403*. In contrast, p.Tyr718* decreased cell numbers (day 1). These discrete phenotypes were associated with an increased expression of both mutant proteins in the cytoplasm. Reduced nuclear/cytoplasmic boundaries were observed in the p.Tyr718* ADNP-mutant line, with this malformation being corrected by the ADNP-derived fragment drug candidate NAP. (4) Conclusions: Distinct impairments characterize different ADNP mutants and reveal aberrant cytoplasmic-nuclear crosstalk. Full article
(This article belongs to the Special Issue Mechanisms of Neurodevelopment and Neurodegeneration)
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20 pages, 4902 KiB  
Article
HIV-Associated Insults Modulate ADAM10 and Its Regulator Sirtuin1 in an NMDA Receptor-Dependent Manner
by Claudia Lopez Lloreda, Sarah Chowdhury, Shivesh Ghura, Elena Alvarez-Periel and Kelly Jordan-Sciutto
Cells 2022, 11(19), 2962; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11192962 - 22 Sep 2022
Cited by 2 | Viewed by 1696
Abstract
Neurologic deficits associated with human immunodeficiency virus (HIV) infection impact about 50% of persons with HIV (PWH). These disorders, termed HIV-associated neurocognitive disorders (HAND), possess neuropathologic similarities to Alzheimer’s disease (AD), including intra- and extracellular amyloid-beta (Aβ) peptide aggregates. Aβ peptide is produced [...] Read more.
Neurologic deficits associated with human immunodeficiency virus (HIV) infection impact about 50% of persons with HIV (PWH). These disorders, termed HIV-associated neurocognitive disorders (HAND), possess neuropathologic similarities to Alzheimer’s disease (AD), including intra- and extracellular amyloid-beta (Aβ) peptide aggregates. Aβ peptide is produced through cleavage of the amyloid precursor protein (APP) by the beta secretase BACE1. However, this is precluded by cleavage of APP by the non-amyloidogenic alpha secretase, ADAM10. Previous studies have found that BACE1 expression was increased in the CNS of PWH with HAND as well as animal models of HAND. Further, BACE1 contributed to neurotoxicity. Yet in in vitro models, the role of ADAM10 and its potential regulatory mechanisms had not been examined. To address this, primary rat cortical neurons were treated with supernatants from HIV-infected human macrophages (HIV/MDMs). We found that HIV/MDMs decreased levels of both ADAM10 and Sirtuin1 (SIRT1), a regulator of ADAM10 that is implicated in aging and in AD. Both decreases were blocked with NMDA receptor antagonists, and treatment with NMDA was sufficient to induce reduction in ADAM10 and SIRT1 protein levels. Furthermore, decreases in SIRT1 protein levels were observed at an earlier time point than the decreases in ADAM10 protein levels, and the reduction in SIRT1 was reversed by proteasome inhibitor MG132. This study indicates that HIV-associated insults, particularly excitotoxicity, contribute to changes of APP secretases by downregulating levels of ADAM10 and its regulator. Full article
(This article belongs to the Special Issue Mechanisms of Neurodevelopment and Neurodegeneration)
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24 pages, 3742 KiB  
Article
β-Glucocerebrosidase Deficiency Activates an Aberrant Lysosome-Plasma Membrane Axis Responsible for the Onset of Neurodegeneration
by Giulia Lunghi, Emma Veronica Carsana, Nicoletta Loberto, Laura Cioccarelli, Simona Prioni, Laura Mauri, Rosaria Bassi, Stefano Duga, Letizia Straniero, Rosanna Asselta, Giulia Soldà, Alessio Di Fonzo, Emanuele Frattini, Manuela Magni, Nara Liessi, Andrea Armirotti, Elena Ferrari, Maura Samarani and Massimo Aureli
Cells 2022, 11(15), 2343; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11152343 - 29 Jul 2022
Cited by 7 | Viewed by 2933
Abstract
β-glucocerebrosidase is a lysosomal hydrolase involved in the catabolism of the sphingolipid glucosylceramide. Biallelic loss of function mutations in this enzyme are responsible for the onset of Gaucher disease, while monoallelic β-glucocerebrosidase mutations represent the first genetic risk factor for Parkinson’s disease. Despite [...] Read more.
β-glucocerebrosidase is a lysosomal hydrolase involved in the catabolism of the sphingolipid glucosylceramide. Biallelic loss of function mutations in this enzyme are responsible for the onset of Gaucher disease, while monoallelic β-glucocerebrosidase mutations represent the first genetic risk factor for Parkinson’s disease. Despite this evidence, the molecular mechanism linking the impairment in β-glucocerebrosidase activity with the onset of neurodegeneration in still unknown. In this frame, we developed two in vitro neuronal models of β-glucocerebrosidase deficiency, represented by mouse cerebellar granule neurons and human-induced pluripotent stem cells-derived dopaminergic neurons treated with the specific β-glucocerebrosidase inhibitor conduritol B epoxide. Neurons deficient for β-glucocerebrosidase activity showed a lysosomal accumulation of glucosylceramide and the onset of neuronal damage. Moreover, we found that neurons react to the lysosomal impairment by the induction of their biogenesis and exocytosis. This latter event was responsible for glucosylceramide accumulation also at the plasma membrane level, with an alteration in lipid and protein composition of specific signaling microdomains. Collectively, our data suggest that β-glucocerebrosidase loss of function impairs the lysosomal compartment, establishing a lysosome–plasma membrane axis responsible for modifications in the plasma membrane architecture and possible alterations of intracellular signaling pathways, leading to neuronal damage. Full article
(This article belongs to the Special Issue Mechanisms of Neurodevelopment and Neurodegeneration)
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12 pages, 2209 KiB  
Article
Expression of Trace Amine-Associated Receptors in the Murine and Human Hippocampus Based on Public Transcriptomic Data
by Nataliia V. Katolikova, Anastasia N. Vaganova, Evgeniya V. Efimova and Raul R. Gainetdinov
Cells 2022, 11(11), 1813; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11111813 - 01 Jun 2022
Cited by 6 | Viewed by 1937
Abstract
Hippocampus is one of the neurogenic zones where adult neurogenesis takes place. This process is quite complex and has a multicomponent regulation. A family of G protein-coupled trace amine-associated receptors (TAARs) was discovered only in 2001, and most of them (TAAR2-TAAR9) were primarily [...] Read more.
Hippocampus is one of the neurogenic zones where adult neurogenesis takes place. This process is quite complex and has a multicomponent regulation. A family of G protein-coupled trace amine-associated receptors (TAARs) was discovered only in 2001, and most of them (TAAR2-TAAR9) were primarily considered olfactory. Recent studies have shown, however, that they are also expressed in the mouse brain, particularly in limbic formations, and can play a role in the regulation of emotional behaviors. The observations in knockout mice indicate that at least two members of the family, TAAR2 and TAAR5, have an impact on the regulation of adult neurogenesis. In the present study, we analyzed the expression of TAARs in the murine and human hippocampus using public RNAseq datasets. Our results indicate a low but detectable level of certain TAARs expression in the hippocampal cells in selected high-quality transcriptomic datasets from both mouse and human samples. At the same time, we observed the difference between humans, where TAAR6 expression was the highest, and murine samples, where TAAR1, TAAR2, TAAR3, TAAR4 and TAAR5 are more pronouncedly expressed. These observations provide further support to the data gained in knockout mice, indicating a role of TAARs in the regulation of adult neurogenesis in the hippocampus. Full article
(This article belongs to the Special Issue Mechanisms of Neurodevelopment and Neurodegeneration)
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13 pages, 1604 KiB  
Article
Neurodevelopmental Syndrome with Intellectual Disability, Speech Impairment, and Quadrupedia Is Associated with Glutamate Receptor Delta 2 Gene Defect
by Anastasia P. Grigorenko, Maria S. Protasova, Alexandra A. Lisenkova, Denis A. Reshetov, Tatiana V. Andreeva, Gilberto De Lima Garcias, Maria Da Graça Martino Roth, Andreas Papassotiropoulos and Evgeny I. Rogaev
Cells 2022, 11(3), 400; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11030400 - 25 Jan 2022
Cited by 3 | Viewed by 4209
Abstract
Bipedalism, speech, and intellect are the most prominent traits that emerged in the evolution of Homo sapiens. Here, we describe a novel genetic cause of an “involution” phenotype in four patients, who are characterized by quadrupedal locomotion, intellectual impairment, the absence of [...] Read more.
Bipedalism, speech, and intellect are the most prominent traits that emerged in the evolution of Homo sapiens. Here, we describe a novel genetic cause of an “involution” phenotype in four patients, who are characterized by quadrupedal locomotion, intellectual impairment, the absence of speech, small stature, and hirsutism, observed in a consanguineous Brazilian family. Using whole-genome sequencing analysis and homozygous genetic mapping, we identified genes bearing homozygous genetic variants and found a homozygous 36.2 kb deletion in the gene of glutamate receptor delta 2 (GRID2) in the patients, resulting in the lack of a coding region from the fifth to the seventh exons. The GRID2 gene is highly expressed in the cerebellum cortex from prenatal development to adulthood, specifically in Purkinje neurons. Deletion in this gene leads to the loss of the alpha chain in the extracellular amino-terminal protein domain (ATD), essential in protein folding and transport from the endoplasmic reticulum (ER) to the cell surface. Then, we studied the evolutionary trajectories of the GRID2 gene. There was no sign of strong selection of the highly conservative GRID2 gene in ancient hominids (Neanderthals and Denisovans) or modern humans; however, according to in silico tests using the Mfold tool, the GRID2 gene possibly gained human-specific mutations that increased the stability of GRID2 mRNA. Full article
(This article belongs to the Special Issue Mechanisms of Neurodevelopment and Neurodegeneration)
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19 pages, 8023 KiB  
Article
Multi-Target Effects of Novel Synthetic Coumarin Derivatives Protecting Aβ-GFP SH-SY5Y Cells against Aβ Toxicity
by Ching-Chia Huang, Kuo-Hsuan Chang, Ya-Jen Chiu, Yi-Ru Chen, Tsai-Hui Lung, Hsiu Mei Hsieh-Li, Ming-Tsan Su, Ying-Chieh Sun, Chiung-Mei Chen, Wenwei Lin and Guey-Jen Lee-Chen
Cells 2021, 10(11), 3095; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10113095 - 09 Nov 2021
Cited by 12 | Viewed by 2602
Abstract
Alzheimer’s disease (AD) is a common neurodegenerative disease presenting with progressive memory and cognitive impairments. One of the pathogenic mechanisms of AD is attributed to the aggregation of misfolded amyloid β (Aβ), which induces neurotoxicity by reducing the expression of brain-derived neurotrophic factor [...] Read more.
Alzheimer’s disease (AD) is a common neurodegenerative disease presenting with progressive memory and cognitive impairments. One of the pathogenic mechanisms of AD is attributed to the aggregation of misfolded amyloid β (Aβ), which induces neurotoxicity by reducing the expression of brain-derived neurotrophic factor (BDNF) and its high-affinity receptor tropomyosin-related kinase B (TRKB) and increasing oxidative stress, caspase-1, and acetylcholinesterase (AChE) activities. Here, we have found the potential of two novel synthetic coumarin derivatives, ZN014 and ZN015, for the inhibition of Aβ and neuroprotection in SH-SY5Y neuroblastoma cell models for AD. In SH-SY5Y cells expressing the GFP-tagged Aβ-folding reporter, both ZN compounds reduced Aβ aggregation, oxidative stress, activities of caspase-1 and AChE, as well as increased neurite outgrowth. By activating TRKB-mediated extracellular signal-regulated kinase (ERK) and AKT serine/threonine kinase 1 (AKT) signaling, these two ZN compounds also upregulated the cAMP-response-element binding protein (CREB) and its downstream BDNF and anti-apoptotic B-cell lymphoma 2 (BCL2). Knockdown of TRKB attenuated the neuroprotective effects of ZN014 and ZN015. A parallel artificial membrane permeability assay showed that ZN014 and ZN015 could be characterized as blood–brain barrier permeable. Our results suggest ZN014 and ZN015 as novel therapeutic candidates for AD and demonstrate that ZN014 and ZN015 reduce Aβ neurotoxicity via pleiotropic mechanisms. Full article
(This article belongs to the Special Issue Mechanisms of Neurodevelopment and Neurodegeneration)
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Review

Jump to: Research

35 pages, 1768 KiB  
Review
Intranasal Peptide Therapeutics: A Promising Avenue for Overcoming the Challenges of Traditional CNS Drug Development
by Meenakshi Bose, Gabriela Farias Quipildor, Michelle E. Ehrlich and Stephen R. Salton
Cells 2022, 11(22), 3629; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11223629 - 16 Nov 2022
Cited by 9 | Viewed by 3585
Abstract
The central nervous system (CNS) has, among all organ systems in the human body, the highest failure rate of traditional small-molecule drug development, ranging from 80–100% depending on the area of disease research. This has led to widespread abandonment by the pharmaceutical industry [...] Read more.
The central nervous system (CNS) has, among all organ systems in the human body, the highest failure rate of traditional small-molecule drug development, ranging from 80–100% depending on the area of disease research. This has led to widespread abandonment by the pharmaceutical industry of research and development for CNS disorders, despite increased diagnoses of neurodegenerative disorders and the continued lack of adequate treatment options for brain injuries, stroke, neurodevelopmental disorders, and neuropsychiatric illness. However, new approaches, concurrent with the development of sophisticated bioinformatic and genomic tools, are being used to explore peptide-based therapeutics to manipulate endogenous pathways and targets, including “undruggable” intracellular protein-protein interactions (PPIs). The development of peptide-based therapeutics was previously rejected due to systemic off-target effects and poor bioavailability arising from traditional oral and systemic delivery methods. However, targeted nose-to-brain, or intranasal (IN), approaches have begun to emerge that allow CNS-specific delivery of therapeutics via the trigeminal and olfactory nerve pathways, laying the foundation for improved alternatives to systemic drug delivery. Here we review a dozen promising IN peptide therapeutics in preclinical and clinical development for neurodegenerative (Alzheimer’s, Parkinson’s), neuropsychiatric (depression, PTSD, schizophrenia), and neurodevelopmental disorders (autism), with insulin, NAP (davunetide), IGF-1, PACAP, NPY, oxytocin, and GLP-1 agonists prominent among them. Full article
(This article belongs to the Special Issue Mechanisms of Neurodevelopment and Neurodegeneration)
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38 pages, 1590 KiB  
Review
Glatiramer Acetate Immunomodulation: Evidence of Neuroprotection and Cognitive Preservation
by Arielle Kasindi, Dieu-Trang Fuchs, Yosef Koronyo, Altan Rentsendorj, Keith L. Black and Maya Koronyo-Hamaoui
Cells 2022, 11(9), 1578; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11091578 - 07 May 2022
Cited by 17 | Viewed by 3939
Abstract
Novel, neuroprotective uses of Copaxone (generic name: glatiramer acetate—GA) are being examined, primarily in neurological conditions involving cognitive decline. GA is a well-studied synthetic copolymer that is FDA-approved for immune-based treatment of relapsing remitting multiple sclerosis (RRMS). Clinical studies have explored the potential [...] Read more.
Novel, neuroprotective uses of Copaxone (generic name: glatiramer acetate—GA) are being examined, primarily in neurological conditions involving cognitive decline. GA is a well-studied synthetic copolymer that is FDA-approved for immune-based treatment of relapsing remitting multiple sclerosis (RRMS). Clinical studies have explored the potential mechanism of action (MOA) and outcomes of GA immunization in patients. Furthermore, results from these and animal studies suggest that GA has a direct immunomodulatory effect on adaptive and innate immune cell phenotypes and responses. These MOAs have been postulated to have a common neuroprotective impact in several neuroinflammatory and neurodegenerative diseases. Notably, several clinical studies report that the use of GA mitigated MS-associated cognitive decline. Its propensity to ameliorate neuro-proinflammatory and degenerative processes ignites increased interest in potential alternate uses such as in age-related macular degeneration (AMD), amyotrophic lateral sclerosis (ALS), and Alzheimer’s disease (AD). Preclinical studies are exploring less frequent subcutaneous administration of GA, such as once weekly or monthly or a single dosing regimen. Indeed, cognitive functions were found to be either preserved, reversed, or improved after the less frequent treatment regimens with GA in animal models of AD. In this systematic review, we examine the potential novel uses of GA across clinical and pre-clinical studies, with evidence for its beneficial impact on cognition. Future investigation in large-size, double-blind clinical trials is warranted to establish the impact of GA immunomodulation on neuroprotection and cognitive preservation in various neurological conditions. Full article
(This article belongs to the Special Issue Mechanisms of Neurodevelopment and Neurodegeneration)
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25 pages, 2346 KiB  
Review
What’s in a Gene? The Outstanding Diversity of MAPT
by Daniel Ruiz-Gabarre, Almudena Carnero-Espejo, Jesús Ávila and Vega García-Escudero
Cells 2022, 11(5), 840; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11050840 - 01 Mar 2022
Cited by 10 | Viewed by 4109
Abstract
Tau protein is a microtubule-associated protein encoded by the MAPT gene that carries out a myriad of physiological functions and has been linked to certain pathologies collectively termed tauopathies, including Alzheimer’s disease, frontotemporal dementia, Huntington’s disease, progressive supranuclear palsy, etc. Alternative splicing is [...] Read more.
Tau protein is a microtubule-associated protein encoded by the MAPT gene that carries out a myriad of physiological functions and has been linked to certain pathologies collectively termed tauopathies, including Alzheimer’s disease, frontotemporal dementia, Huntington’s disease, progressive supranuclear palsy, etc. Alternative splicing is a physiological process by which cells generate several transcripts from one single gene and may in turn give rise to different proteins from the same gene. MAPT transcripts have been proven to be subjected to alternative splicing, generating six main isoforms in the central nervous system. Research throughout the years has demonstrated that the splicing landscape of the MAPT gene is far more complex than that, including at least exon skipping events, the use of 3′ and 5′ alternative splice sites and, as has been recently discovered, also intron retention. In addition, MAPT alternative splicing has been showed to be regulated spatially and developmentally, further evidencing the complexity of the gene’s splicing regulation. It is unclear what would drive the need for the existence of so many isoforms encoded by the same gene, but a wide range of functions have been ascribed to these Tau isoforms, both in physiology and pathology. In this review we offer a comprehensive up-to-date exploration of the mechanisms leading to the outstanding diversity of isoforms expressed from the MAPT gene and the functions in which such isoforms are involved, including their potential role in the onset and development of tauopathies such as Alzheimer’s disease. Full article
(This article belongs to the Special Issue Mechanisms of Neurodevelopment and Neurodegeneration)
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20 pages, 2090 KiB  
Review
Experimental Treatments for Oedema in Spinal Cord Injury: A Systematic Review and Meta-Analysis
by Emma Masterman and Zubair Ahmed
Cells 2021, 10(10), 2682; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10102682 - 07 Oct 2021
Cited by 5 | Viewed by 2562
Abstract
The incidence of spinal cord injury (SCI) is ever-growing, resulting in life-changing neurological deficits which can have devastating long-term impacts on a person’s quality of life. There is an unmet clinical need for a treatment which will prevent progression of the injury, allowing [...] Read more.
The incidence of spinal cord injury (SCI) is ever-growing, resulting in life-changing neurological deficits which can have devastating long-term impacts on a person’s quality of life. There is an unmet clinical need for a treatment which will prevent progression of the injury, allowing improved axonal regeneration and functional recovery to occur. The initial mechanical insult, followed by a cascade of secondary mechanisms, leads to the exacerbation and remodelling of the lesion site, thus inhibiting neurological recovery. Oedema rapidly accumulates following SCI and contributes to the detrimental pathophysiology and worsens functional outcomes. This study systematically reviewed the current experimental treatments being explored in the field of SCI, which specifically target oedema. Abiding by PRISMA guidelines and strict inclusion criteria, 14 studies were identified and analysed from three online databases (PubMed, Web of Science and EMBASE). As a result, we identified three key modalities which attenuate oedema: selective inhibition of the main water channel protein, aquaporin 4 (AQP4), modulation of inflammation and surgical interventions. Collectively, however, they all result in the downregulation of AQP4, which crucially leads to a reduction in oedema and improved functional outcomes. We concluded that trifluoperazine (TFP), a calmodulin kinase inhibitor which prevents the cell-surface localisation of AQP4, was the most efficacious treatment, significantly eliminating oedema within 7 days of administration. To date, this study is the most concise analysis of current experimental treatments for oedema, exposing its molecular mechanisms and assessing potential therapeutic pathways for future research. Full article
(This article belongs to the Special Issue Mechanisms of Neurodevelopment and Neurodegeneration)
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22 pages, 2491 KiB  
Review
Inflammatory Cascade in Alzheimer’s Disease Pathogenesis: A Review of Experimental Findings
by Jade de Oliveira, Ewa Kucharska, Michelle Lima Garcez, Matheus Scarpatto Rodrigues, João Quevedo, Ines Moreno-Gonzalez and Josiane Budni
Cells 2021, 10(10), 2581; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10102581 - 28 Sep 2021
Cited by 42 | Viewed by 5844
Abstract
Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Most AD patients develop the disease in late life, named late onset AD (LOAD). Currently, the most recognized explanation for AD pathology is the amyloid cascade hypothesis. It is assumed that amyloid beta [...] Read more.
Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Most AD patients develop the disease in late life, named late onset AD (LOAD). Currently, the most recognized explanation for AD pathology is the amyloid cascade hypothesis. It is assumed that amyloid beta (Aβ) aggregation and deposition are critical pathogenic processes in AD, leading to the formation of amyloid plaques, as well as neurofibrillary tangles, neuronal cell death, synaptic degeneration, and dementia. In LOAD, the causes of Aβ accumulation and neuronal loss are not completely clear. Importantly, the blood–brain barrier (BBB) disruption seems to present an essential role in the induction of neuroinflammation and consequent AD development. In addition, we propose that the systemic inflammation triggered by conditions like metabolic diseases or infections are causative factors of BBB disruption, coexistent inflammatory cascade and, ultimately, the neurodegeneration observed in AD. In this regard, the use of anti-inflammatory molecules could be an interesting strategy to treat, delay or even halt AD onset and progression. Herein, we review the inflammatory cascade and underlying mechanisms involved in AD pathogenesis and revise the anti-inflammatory effects of compounds as emerging therapeutic drugs against AD. Full article
(This article belongs to the Special Issue Mechanisms of Neurodevelopment and Neurodegeneration)
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Review
Stem Cells: Innovative Therapeutic Options for Neurodegenerative Diseases?
by Gabriele Bonaventura, Antonio Munafò, Carlo Maria Bellanca, Valentina La Cognata, Rosario Iemmolo, Giuseppe Antonino Attaguile, Rosaria Di Mauro, Giulia Di Benedetto, Giuseppina Cantarella, Maria Luisa Barcellona, Sebastiano Cavallaro and Renato Bernardini
Cells 2021, 10(8), 1992; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10081992 - 05 Aug 2021
Cited by 18 | Viewed by 5704
Abstract
Neurodegenerative diseases are characterized by the progressive loss of structure and/or function of both neurons and glial cells, leading to different degrees of pathology and loss of cognition. The hypothesis of circuit reconstruction in the damaged brain via direct cell replacement has been [...] Read more.
Neurodegenerative diseases are characterized by the progressive loss of structure and/or function of both neurons and glial cells, leading to different degrees of pathology and loss of cognition. The hypothesis of circuit reconstruction in the damaged brain via direct cell replacement has been pursued extensively so far. In this context, stem cells represent a useful option since they provide tissue restoration through the substitution of damaged neuronal cells with exogenous stem cells and create a neuro-protective environment through the release of bioactive molecules for healthy neurons, as well. These peculiar properties of stem cells are opening to potential therapeutic strategies for the treatment of severe neurodegenerative disorders, for which the absence of effective treatment options leads to an increasingly socio-economic burden. Currently, the introduction of new technologies in the field of stem cells and the implementation of alternative cell tissues sources are pointing to exciting frontiers in this area of research. Here, we provide an update of the current knowledge about source and administration routes of stem cells, and review light and shadows of cells replacement therapy for the treatment of the three main neurodegenerative disorders (Amyotrophic lateral sclerosis, Parkinson’s, and Alzheimer’s disease). Full article
(This article belongs to the Special Issue Mechanisms of Neurodevelopment and Neurodegeneration)
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