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Advances in Neurodegenerative Diseases Research and Therapy
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Advances in Neurodegenerative Diseases Research and Therapy

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 17897

Special Issue Editors

Prof. Dr. Maria Eriksdotter

E-Mail Website
Guest Editor
1. Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institute, 14183 Huddinge, Sweden
2. Theme Aging, Karolinska University Hospital, 141 86 Huddinge, Sweden
Interests: nerve growth factor; neurotrophins; Alzheimer’s disease; therapy; encapsulated cell biodelivery; Swedish Dementia Registry
Dr. Sumonto Mitra

E-Mail Website
Guest Editor
Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institute, 14183 Huddinge, Sweden
Interests: nerve growth factor; neurotrophins; Alzheimer’s disease; therapy; encapsulated cell biodelivery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Degenerative diseases of the nervous system affect millions of people worldwide and have limited therapeutic interventions available even to the present day, since the blood–brain barrier restricts the passage of most drug candidates into the brain tissue. The term 'neurodegenerative disease' is often used as an umbrella term which includes various debilitating conditions which affects the brain, including Alzheimer's, Parkinson's, Huntington's, etc. Previous studies focused on neuronal degeneration as the primary cause of these diseases, but recent evidence points towards the contribution of glial cells in maintaining a physiological and functioning neural output. Although these diseases have different pathological markers and clinical symptoms, they share common molecular pathways including gliosis, proteostasis, inflammation, metabolic alterations, etc. It has been evident that understanding the molecular changes occurring during the development and progression of neurodegenerative diseases may led to the development of effective therapeutic interventions.

This Special Issue entitled 'Advances in Neurodegenerative Diseases Research and Therapy' invites original research and review articles to provide latest update on the molecular changes associated with neurodegenerative diseases. Special focus would also be on the development of 'clinically relevant' therapeutic strategies against neurodegenerative diseases (including optimization studies, clinical efficacy studies, biomarker evaluation, drug delivery, etc).

Prof. Dr. Maria Eriksdotter
Dr. Sumonto Mitra
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neurodegenerative diseases
  • therapy
  • molecular mechanisms
  • neuron
  • astrocytes
  • microglia
  • inflammation
  • brain
  • drug delivery

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Published Papers (6 papers)

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Research

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18 pages, 2121 KiB  
Article
Systemic and Peripheral Mechanisms of Cortical Stimulation-Induced Analgesia and Refractoriness in a Rat Model of Neuropathic Pain
by Danielle V. Assis, Ana Carolina P. Campos, Amanda F. N. Paschoa, Talita F. Santos, Erich T. Fonoff and Rosana L. Pagano
Int. J. Mol. Sci. 2023, 24(9), 7796; https://doi.org/10.3390/ijms24097796 - 25 Apr 2023
Cited by 4 | Viewed by 1976
Abstract
Epidural motor cortex stimulation (MCS) is an effective treatment for refractory neuropathic pain; however, some individuals are unresponsive. In this study, we correlated the effectiveness of MCS and refractoriness with the expression of cytokines, neurotrophins, and nociceptive mediators in the dorsal root ganglion [...] Read more.
Epidural motor cortex stimulation (MCS) is an effective treatment for refractory neuropathic pain; however, some individuals are unresponsive. In this study, we correlated the effectiveness of MCS and refractoriness with the expression of cytokines, neurotrophins, and nociceptive mediators in the dorsal root ganglion (DRG), sciatic nerve, and plasma of rats with sciatic neuropathy. MCS inhibited hyperalgesia and allodynia in two-thirds of the animals (responsive group), and one-third did not respond (refractory group). Chronic constriction injury (CCI) increased IL-1β in the nerve and DRG, inhibited IL-4, IL-10, and IL-17A in the nerve, decreased β-endorphin, and enhanced substance P in the plasma, compared to the control. Responsive animals showed decreased NGF and increased IL-6 in the nerve, accompanied by restoration of local IL-10 and IL-17A and systemic β-endorphin. Refractory animals showed increased TNF-α and decreased IFNγ in the nerve, along with decreased TNF-α and IL-17A in the DRG, maintaining low levels of systemic β-endorphin. Our findings suggest that the effectiveness of MCS depends on local control of inflammatory and neurotrophic changes, accompanied by recovery of the opioidergic system observed in neuropathic conditions. So, understanding the refractoriness to MCS may guide an improvement in the efficacy of the technique, thus benefiting patients with persistent neuropathic pain. Full article
(This article belongs to the Special Issue Advances in Neurodegenerative Diseases Research and Therapy)
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22 pages, 3164 KiB  
Article
Anp32a Promotes Neuronal Regeneration after Spinal Cord Injury of Zebrafish Embryos
by Hung-Chieh Lee, Wei-Lin Lai, Cheng-Yung Lin, Chih-Wei Zeng, Jin-Chuan Sheu, Tze-Bin Chou and Huai-Jen Tsai
Int. J. Mol. Sci. 2022, 23(24), 15921; https://doi.org/10.3390/ijms232415921 - 14 Dec 2022
Cited by 6 | Viewed by 3089
Abstract
After spinal cord injury (SCI) in mammals, neuronal regeneration is limited; in contrast, such regeneration occurs quickly in zebrafish. Member A of the acidic nuclear phosphoprotein 32 (ANP32a) family is involved in neuronal development, but its function is controversial, and its [...] Read more.
After spinal cord injury (SCI) in mammals, neuronal regeneration is limited; in contrast, such regeneration occurs quickly in zebrafish. Member A of the acidic nuclear phosphoprotein 32 (ANP32a) family is involved in neuronal development, but its function is controversial, and its involvement in zebrafish SCI remains unknown. To determine the role of zebrafish ANP32a in the neuronal regeneration of SCI embryos, we microinjected ANP32a mRNA into embryos from zebrafish transgenic line Tg(mnx1:GFP) prior to SCI. Compared to control SCI embryos, the results showed that the regeneration of spinal cord and resumption of swimming capability were promoted by the overexpression of ANP32a mRNA but reduced by its knockdown. We next combined fluorescence-activated cell sorting with immunochemical staining of anti-GFAP and immunofluorescence staining against anti-PH3 on Tg(gfap:GFP) SCI embryos. The results showed that ANP32a promoted the proliferation and cell number of radial glial cells at the injury epicenter at 24 h post-injury (hpi). Moreover, when we applied BrdU labeling to SCI embryos derived from crossing the Tg(gfap:GFP) and Tg(mnx1:TagRFP) lines, we found that both radial glial cells and motor neurons had proliferated, along with their increased cell numbers in Anp32a-overexpression SCI-embryos. On this basis, we conclude that ANP32a plays a positive role in the regeneration of zebrafish SCI embryos. Full article
(This article belongs to the Special Issue Advances in Neurodegenerative Diseases Research and Therapy)
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20 pages, 2889 KiB  
Article
Microglia Impairs Proliferation and Induces Senescence In-Vitro in NGF Releasing Cells Used in Encapsulated Cell Biodelivery for Alzheimer’s Disease Therapy
by Sumonto Mitra, Ruchi Gera, Julia Sundheimer, Marine Lemee, Lars U. Wahlberg, Bengt Linderoth, Maria Eriksdotter and Homira Behbahani
Int. J. Mol. Sci. 2022, 23(16), 9011; https://doi.org/10.3390/ijms23169011 - 12 Aug 2022
Cited by 3 | Viewed by 2744
Abstract
There is no cure yet available for Alzheimer’s disease (AD). We recently optimized encapsulated cell biodelivery (ECB) devices releasing human mature nerve growth factor (hmNGF), termed ECB-NGF, to the basal forebrain of AD patients. The ECB-NGF delivery resulted in increased CSF cholinergic markers, [...] Read more.
There is no cure yet available for Alzheimer’s disease (AD). We recently optimized encapsulated cell biodelivery (ECB) devices releasing human mature nerve growth factor (hmNGF), termed ECB-NGF, to the basal forebrain of AD patients. The ECB-NGF delivery resulted in increased CSF cholinergic markers, improved glucose metabolism, and positive effects on cognition in AD patients. However, some ECB-NGF implants showed altered hmNGF release post-explantation. To optimize the ECB-NGF platform for future therapeutic purposes, we initiated in-vitro optimization studies by exposing ECB-NGF devices to physiological factors present within the AD brain. We report here that microglia cells can impair hmNGF release from ECB-NGF devices in-vitro, which can be reversed by transferring the devices to fresh culture medium. Further, we exposed the hmNGF secreting human ARPE-19 cell line (NGC0211) to microglia (HMC3) conditioned medium (MCM; untreated or treated with IL-1β/IFNγ/Aβ40/Aβ42), and evaluated biochemical stress markers (ROS, GSH, ΔΨm, and Alamar Blue assay), cell death indicators (Annexin-V/PI), cell proliferation (CFSE retention and Ki67) and senescence markers (SA-β-gal) in NGC0211 cells. MCMs from activated microglia reduced cell proliferation and induced cell senescence in NGC0211 cells, which otherwise resist biochemical alterations and cell death. These data indicate a critical but reversible impact of activated microglia on NGC0211 cells. Full article
(This article belongs to the Special Issue Advances in Neurodegenerative Diseases Research and Therapy)
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17 pages, 5064 KiB  
Article
Seizures in PPT1 Knock-In Mice Are Associated with Inflammatory Activation of Microglia
by Xusheng Zhang, Mengting Wang, Bingyan Feng, Qiuyu Zhang, Jia Tong, Mingyong Wang, Chengbiao Lu and Shiyong Peng
Int. J. Mol. Sci. 2022, 23(10), 5586; https://doi.org/10.3390/ijms23105586 - 17 May 2022
Cited by 9 | Viewed by 2866
Abstract
Infantile neuronal ceroid lipofuscinosis (INCL), the most severe form of neuronal ceroid lipofuscinoses, is caused by mutations in the lysosomal enzyme palmitoyl protein thioesterase 1 (PPT1). Typical symptoms of this disease include progressive psychomotor developmental retardation, visual failure, seizures, and premature death. Here, [...] Read more.
Infantile neuronal ceroid lipofuscinosis (INCL), the most severe form of neuronal ceroid lipofuscinoses, is caused by mutations in the lysosomal enzyme palmitoyl protein thioesterase 1 (PPT1). Typical symptoms of this disease include progressive psychomotor developmental retardation, visual failure, seizures, and premature death. Here, we investigated seizure activity and relevant pathological changes in PPT1 knock-in mice (PPT1 KI). The behavior studies in this study demonstrated that PPT1 KI mice had no significant seizure activity until 7 months of age, and local field potentials also displayed epileptiform activity at the same age. The expression levels of Iba-1 and CD68 demonstrated, by Western blot analysis, the inflammatory cytokine TNF-α content measured with enzyme-linked immunosorbent assay, and the number of microglia demonstrated by immunohistochemistry (IHC) were significantly increased at age of 7 months, all of which indicate microglia activation at an age of seizure onset. The increased expression of GFAP were seen at an earlier age of 4 months, and such an increase reached its peak at age of 6 months, indicating that astrocyte activation precedes microglia. The purinergic P2X7 receptor (P2X7R) is an ATP-sensitive ionic channel that is highly expressed in microglia and is fundamental to microglial activation, proliferation, cytokines release and epilepsy. We show that the ATP concentration in hippocampal tissue in PPT1 KI mice was increased using an enhanced ATP assay kit and demonstrated that the antagonist of P2X7R, A-438079, significantly reduced seizures in PPT1 KI mice. In contrast to glial cell activation and proliferation, a significant reduction in synaptic proteins GABAAR was seen in PPT1 KI mice. These results indicate that seizure in PPT1 KI mice may be associated with microglial activation involved in ATP-sensitive P2X7R signaling and impaired inhibitory neurotransmission. Full article
(This article belongs to the Special Issue Advances in Neurodegenerative Diseases Research and Therapy)
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17 pages, 3926 KiB  
Article
Single Cell Analysis of Reversibility of the Cell Death Program in Ethanol-Treated Neuronal PC12 Cells
by Wenting You, Tos T. J. M. Berendschot, Kèvin Knoops, Marc A. M. J. van Zandvoort, Carroll A. B. Webers, Chris P. M. Reutelingsperger and Theo G. M. F. Gorgels
Int. J. Mol. Sci. 2022, 23(5), 2650; https://doi.org/10.3390/ijms23052650 - 28 Feb 2022
Cited by 10 | Viewed by 3314
Abstract
Neurodegenerative diseases are generally characterized clinically by the selective loss of a distinct subset of neurons and a slow progressive course. Mounting evidence in vivo indicates that large numbers of neurons pass through a long period of injury and dysfunction before the actual [...] Read more.
Neurodegenerative diseases are generally characterized clinically by the selective loss of a distinct subset of neurons and a slow progressive course. Mounting evidence in vivo indicates that large numbers of neurons pass through a long period of injury and dysfunction before the actual death of the cells. Whether these dying neurons can be rescued and return to a normal, functional state is uncertain. In the present study, we explored the reversibility of the neuronal cell death pathway at various stages by monitoring the dynamics of single cells with high-resolution live-cell spinning disk confocal microscopy in an in vitro neuronal cell death model. We exposed differentiated neuronal PC12 cells to ethanol as our cell death model. Results showed that exposure to 5% ethanol for 24 h induced cell death in >70% of the cells. Ethanol treatment for 3 h already induced cellular changes and damage such as reactive oxygen species generation, elevation of intracellular Ca2+ level, phosphatidylserine exposure, nuclear shrinkage, DNA damage, mitochondrial fragmentation and membrane potential loss, and retraction of neurites. These phenomena are often associated with programmed cell death. Importantly, after removing ethanol and further culturing these damaged cells in fresh culture medium, cells recovered from all these cell injuries and generated new neurites. Moreover, results indicated that this recovery was not dependent on exogenous NGF and other growth factors in the cell culture medium. Overall, our results suggest that targeting dying neurons can be an effective therapeutic strategy in neurodegenerative diseases. Full article
(This article belongs to the Special Issue Advances in Neurodegenerative Diseases Research and Therapy)
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Review

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15 pages, 1054 KiB  
Review
The Emerging Key Role of the mGluR1-PKCγ Signaling Pathway in the Pathogenesis of Spinocerebellar Ataxias: A Neurodevelopmental Viewpoint
by Qin-Wei Wu and Josef P. Kapfhammer
Int. J. Mol. Sci. 2022, 23(16), 9169; https://doi.org/10.3390/ijms23169169 - 15 Aug 2022
Cited by 4 | Viewed by 2604
Abstract
Spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal dominantly inherited progressive disorders with degeneration and dysfunction of the cerebellum. Although different subtypes of SCAs are classified according to the disease-associated causative genes, the clinical syndrome of the ataxia is shared, pointing towards [...] Read more.
Spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal dominantly inherited progressive disorders with degeneration and dysfunction of the cerebellum. Although different subtypes of SCAs are classified according to the disease-associated causative genes, the clinical syndrome of the ataxia is shared, pointing towards a possible convergent pathogenic pathway among SCAs. In this review, we summarize the role of SCA-associated gene function during cerebellar Purkinje cell development and discuss the relationship between SCA pathogenesis and neurodevelopment. We will summarize recent studies on molecules involved in SCA pathogenesis and will focus on the mGluR1-PKCγ signaling pathway evaluating the possibility that this might be a common pathway which contributes to these diseases. Full article
(This article belongs to the Special Issue Advances in Neurodegenerative Diseases Research and Therapy)
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