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Molecular Research on Neurodegenerative Diseases 2.0
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Molecular Research on Neurodegenerative Diseases 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 59467

Special Issue Editors

Prof. Dr. Cesar Borlongan

E-Mail Website
Guest Editor
Department of Neurosurgery, MDC 78, University of South Florida College Medicine, Tampa, FL 33612, USA
Interests: stem cell therapy; stroke; neonatal hypoxic-ischemic injury; Parkinson's disease; traumatic brain injury; translational research
Special Issues, Collections and Topics in MDPI journals
Dr. Eleonora Napoli

E-Mail Website
Guest Editor
Department of Neurology, School of Medicine, University of California Davis, 4860 Y Street, Suite 3700, Sacramento, CA 95817, USA
Interests: bioenergetics; mitochondrial biology; oxidative stress; neurodegeneration; ASD; Rapid-onset dystonia parkinsonism (RDP); ATP1A3-related neurological disorders

Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous Special Issue "Molecular Research on Neurodegenerative Diseases" (https://www.mdpi.com/journal/ijms/special_issues/neurodegenerative_dis).

Many neurological disorders have been characterized by neurodegenerative processes, with key molecular signaling pathways participating in the cascade of cell death events. Even brain diseases, traditionally considered as acute central nervous system injury, such as stroke and traumatic brain injury, have now been recognized as presenting with major pathological components, known as hallmarks of chronic neurodegeneration. Among the many molecular signatures of neurodegeneration, specific molecules associated with inflammation and mitochondrial dysfunction have been implicated as pivotal checkpoints in the propagation of cell death mechanisms, yet also indicated as equally involved as robust targets for anchoring cell survival therapeutics. This Special Issue is dedicated to the recent research progress in deciphering molecular pathways mediating cell death and cell survival in neurodegeneration and its treatment. The goal is to provide an in-depth understanding of the underlying central role of neurodegeneration in brain diseases, and to exploit such knowledge in the development of novel molecule-based therapies against neurodegenerative disorders.

Prof. Dr. Cesar Borlongan
Dr. Eleonora Napoli
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

  • neurological disorders
  • stroke
  • traumatic brain injury
  • neurodegeneration
  • Parkinson's disease
  • molecular pathways

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Published Papers (16 papers)

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Editorial

Jump to: Research, Review, Other

6 pages, 224 KiB  
Editorial
Molecular, Translational and Clinical Research on the Two Most Common Forms of Neurodegenerative Dementia: Alzheimer’s Disease and Dementia with Lewy Bodies
by Eleonora Napoli
Int. J. Mol. Sci. 2023, 24(9), 7996; https://doi.org/10.3390/ijms24097996 - 28 Apr 2023
Cited by 1 | Viewed by 986
Abstract
While not a specific disease, dementia is a term used to describe the deterioration of cognitive function beyond what would be expected because of natural biological aging [...] Full article
(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 2.0)

Research

Jump to: Editorial, Review, Other

15 pages, 4294 KiB  
Article
Treadmill Exercise Ameliorates Adult Hippocampal Neurogenesis Possibly by Adjusting the APP Proteolytic Pathway in APP/PS1 Transgenic Mice
by Haizhen Yu, Chenfei Zhang, Jie Xia and Bo Xu
Int. J. Mol. Sci. 2021, 22(17), 9570; https://doi.org/10.3390/ijms22179570 - 03 Sep 2021
Cited by 16 | Viewed by 2782
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder known to cause cognitive impairment among the elderly worldwide. Although physical exercise-induced adult hippocampal neurogenesis (AHN) improves cognition, understanding its underlying molecular mechanisms requires further investigation using AD mouse models. In this present work, we subjected [...] Read more.
Alzheimer’s disease (AD) is a neurodegenerative disorder known to cause cognitive impairment among the elderly worldwide. Although physical exercise-induced adult hippocampal neurogenesis (AHN) improves cognition, understanding its underlying molecular mechanisms requires further investigation using AD mouse models. In this present work, we subjected amyloid precursor protein (APP)/PS1 mice to a 12-week aerobic treadmill exercise to investigate AHN and its potential mechanisms. We divided 3-month-old littermates wild-type and APP/PS1 transgenic male mice into four groups, and the exercise groups performed 12-week treadmill exercise. Next, we evaluated the influence of treadmill exercise on learning and memory capacity, AHN, and APP proteolytic pathway-related factors. As per our results, the treadmill exercise was able to improve the hippocampal microenvironment in APP/PS1 mice probably by regulating various neurotrophic factors and secretases resulting in APP cleavage through a non-amyloidogenic pathway, which seems to further promote new cell proliferation, survival, and differentiation, enhancing hippocampal neurogenesis. All of these effects ameliorate learning and memory capacity. This study provides a theoretical and experimental basis for understanding AHN in an AD mouse model, which is beneficial for preventing and treating AD. Full article
(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 2.0)
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16 pages, 1755 KiB  
Article
Brain Atrophy and White Matter Damage Linked to Peripheral Bioenergetic Deficits in the Neurodegenerative Disease FXTAS
by Jun Yi Wang, Eleonora Napoli, Kyoungmi Kim, Yingratana A. McLennan, Randi J. Hagerman and Cecilia Giulivi
Int. J. Mol. Sci. 2021, 22(17), 9171; https://doi.org/10.3390/ijms22179171 - 25 Aug 2021
Cited by 9 | Viewed by 2109
Abstract
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder affecting subjects (premutation carriers) with a 55-200 CGG-trinucleotide expansion in the 5′UTR of the fragile X mental retardation 1 gene (FMR1) typically after age 50. As both the presence of white matter [...] Read more.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder affecting subjects (premutation carriers) with a 55-200 CGG-trinucleotide expansion in the 5′UTR of the fragile X mental retardation 1 gene (FMR1) typically after age 50. As both the presence of white matter hyperintensities (WMHs) and atrophied gray matter on magnetic resonance imaging (MRI) are linked to age-dependent decline in cognition, here we tested whether MRI outcomes (WMH volume (WMHV) and brain volume) were correlated with mitochondrial bioenergetics from peripheral blood monocytic cells in 87 carriers with and without FXTAS. As a parameter assessing cumulative damage, WMHV was correlated to both FXTAS stages and age, and brain volume discriminated between carriers and non-carriers. Similarly, mitochondrial mass and ATP production showed an age-dependent decline across all participants, but in contrast to WMHV, only FADH2-linked ATP production was significantly reduced in carriers vs. non-carriers. In carriers, WMHV negatively correlated with ATP production sustained by glucose-glutamine and FADH2-linked substrates, whereas brain volume was positively associated with the latter and mitochondrial mass. The observed correlations between peripheral mitochondrial bioenergetics and MRI findings—and the lack of correlations with FXTAS diagnosis/stages—may stem from early brain bioenergetic deficits even before overt FXTAS symptoms and/or imaging findings. Full article
(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 2.0)
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12 pages, 2387 KiB  
Article
Bone Fracture Enhanced Blood-Brain Barrier Breakdown in the Hippocampus and White Matter Damage of Stroke Mice
by Jinhao Huang, Haiyan Lyu, Kang Huo, Leandro B. Do Prado, Chaoliang Tang, Zhanqiang Wang, Qifeng Li, Julia Wong and Hua Su
Int. J. Mol. Sci. 2020, 21(22), 8481; https://doi.org/10.3390/ijms21228481 - 11 Nov 2020
Cited by 3 | Viewed by 1827
Abstract
Background: Tibia fracture (BF) before stroke shortly causes long-term post-stroke memory dysfunction in mice. The mechanism is unclear. We hypothesize that BF enhances neuroinflammation and blood brain barrier (BBB) breakdown in the hippocampus and white matter (WM) damage. Methods: Mice were assigned to [...] Read more.
Background: Tibia fracture (BF) before stroke shortly causes long-term post-stroke memory dysfunction in mice. The mechanism is unclear. We hypothesize that BF enhances neuroinflammation and blood brain barrier (BBB) breakdown in the hippocampus and white matter (WM) damage. Methods: Mice were assigned to groups: BF, stroke, BF+stroke (BF 6 h before stroke) and sham. BBB integrity was analyzed 3 days after the surgeries and WM injury was analyzed 3 days and 8 weeks after the surgeries. Results: Stroke and BF+stroke groups had more activated microglia/macrophages and lower levels of claudin-5 in the ipsilateral hippocampi than the BF group. BF+stroke group had the highest number microglia/macrophages and the lowest level of claudin-5 among all groups and had fewer pericytes than BF group. Stroke and BF+stroke groups had smaller WM areas in the ipsilateral basal ganglia than the sham group 8 weeks after the injuries. The BF+stroke group also had smaller WM areas in the ipsilateral than sham and BF groups 3 days after the injuries and in the contralateral basal ganglia than stroke and BF groups 8 weeks after the injuries. Conclusions: BF exacerbates neuroinflammation and BBB leakage in the hippocampus and WM damage in basal ganglia, which could contribute to the long-lasting memory dysfunction in BF+stroke mice. Full article
(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 2.0)
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16 pages, 3690 KiB  
Article
Ethionamide Preconditioning Enhances the Proliferation and Migration of Human Wharton’s Jelly-Derived Mesenchymal Stem Cells
by Na-Hee Lee, Su Hyeon Myeong, Hyo Jin Son, Jung Won Hwang, Na Kyung Lee, Jong Wook Chang and Duk L. Na
Int. J. Mol. Sci. 2020, 21(19), 7013; https://doi.org/10.3390/ijms21197013 - 23 Sep 2020
Cited by 11 | Viewed by 2855
Abstract
Mesenchymal stem cells (MSCs) are a useful source for cell-based therapy of a variety of immune-mediated diseases, including neurodegenerative disorders. However, poor migration ability and survival rate of MSCs after brain transplantation hinder the therapeutic effects in the disease microenvironment. Therefore, we attempted [...] Read more.
Mesenchymal stem cells (MSCs) are a useful source for cell-based therapy of a variety of immune-mediated diseases, including neurodegenerative disorders. However, poor migration ability and survival rate of MSCs after brain transplantation hinder the therapeutic effects in the disease microenvironment. Therefore, we attempted to use a preconditioning strategy with pharmacological agents to improve the cell proliferation and migration of MSCs. In this study, we identified ethionamide via the screening of a drug library, which enhanced the proliferation of MSCs. Preconditioning with ethionamide promoted the proliferation of Wharton’s jelly-derived MSCs (WJ-MSCs) by activating phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase/extracellular signal-regulated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK)1/2 signaling. Preconditioning with ethionamide also enhanced the migration ability of MSCs by upregulating expression of genes associated with migration, such as C-X-C motif chemokine receptor 4 (CXCR4) and C-X-C motif chemokine ligand 12 (CXCL12). Furthermore, preconditioning with ethionamide stimulated the secretion of paracrine factors, including neurotrophic and growth factors in MSCs. Compared to naïve MSCs, ethionamide-preconditioned MSCs (ETH-MSCs) were found to survive longer in the brain after transplantation. These results suggested that enhancing the biological process of MSCs induced by ethionamide preconditioning presents itself as a promising strategy for enhancing the effectiveness of MSCs-based therapies. Full article
(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 2.0)
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18 pages, 1521 KiB  
Article
Proteomic Characterization of the Olfactory Molecular Imbalance in Dementia with Lewy Bodies
by Mercedes Lachén-Montes, Naroa Mendizuri, Domitille Schvartz, Joaquín Fernández-Irigoyen, Jean Charles Sánchez and Enrique Santamaría
Int. J. Mol. Sci. 2020, 21(17), 6371; https://doi.org/10.3390/ijms21176371 - 02 Sep 2020
Cited by 7 | Viewed by 2108
Abstract
Olfactory dysfunction is one of the prodromal symptoms in dementia with Lewy bodies (DLB). However, the molecular pathogenesis associated with decreased smell function remains largely undeciphered. We generated quantitative proteome maps to detect molecular alterations in olfactory bulbs (OB) derived from DLB subjects [...] Read more.
Olfactory dysfunction is one of the prodromal symptoms in dementia with Lewy bodies (DLB). However, the molecular pathogenesis associated with decreased smell function remains largely undeciphered. We generated quantitative proteome maps to detect molecular alterations in olfactory bulbs (OB) derived from DLB subjects compared to neurologically intact controls. A total of 3214 olfactory proteins were quantified, and 99 proteins showed significant alterations in DLB cases. Protein interaction networks disrupted in DLB indicated an imbalance in translation and the synaptic vesicle cycle. These alterations were accompanied by alterations in AKT/MAPK/SEK1/p38 MAPK signaling pathways that showed a distinct expression profile across the OB–olfactory tract (OT) axis. Taken together, our data partially reflect the missing links in the biochemical understanding of olfactory dysfunction in DLB. Full article
(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 2.0)
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13 pages, 3116 KiB  
Article
Liraglutide Suppresses Tau Hyperphosphorylation, Amyloid Beta Accumulation through Regulating Neuronal Insulin Signaling and BACE-1 Activity
by Salinee Jantrapirom, Wutigri Nimlamool, Nipon Chattipakorn, Siriporn Chattipakorn, Piya Temviriyanukul, Woorawee Inthachat, Piyarat Govitrapong and Saranyapin Potikanond
Int. J. Mol. Sci. 2020, 21(5), 1725; https://doi.org/10.3390/ijms21051725 - 03 Mar 2020
Cited by 31 | Viewed by 4187
Abstract
Neuronal insulin resistance is a significant feature of Alzheimer’s disease (AD). Accumulated evidence has revealed the possible neuroprotective mechanisms of antidiabetic drugs in AD. Liraglutide, a glucagon-like peptide-1 (GLP-1) analog and an antidiabetic agent, has a benefit in improving a peripheral insulin resistance. [...] Read more.
Neuronal insulin resistance is a significant feature of Alzheimer’s disease (AD). Accumulated evidence has revealed the possible neuroprotective mechanisms of antidiabetic drugs in AD. Liraglutide, a glucagon-like peptide-1 (GLP-1) analog and an antidiabetic agent, has a benefit in improving a peripheral insulin resistance. However, the neuronal effect of liraglutide on the model of neuronal insulin resistance with Alzheimer’s formation has not been thoroughly investigated. The present study discovered that liraglutide alleviated neuronal insulin resistance and reduced beta-amyloid formation and tau hyperphosphorylation in a human neuroblostoma cell line, SH-SY5Y. Liraglutide could effectively reverse deleterious effects of insulin overstimulation. In particular, the drug reversed the phosphorylation status of insulin receptors and its major downstream signaling molecules including insulin receptor substrate 1 (IRS-1), protein kinase B (AKT), and glycogen synthase kinase 3 beta (GSK-3β). Moreover, liraglutide reduced the activity of beta secretase 1 (BACE-1) enzyme, which then decreased the formation of beta-amyloid in insulin-resistant cells. This indicated that liraglutide can reverse the defect of phosphorylation status of insulin signal transduction but also inhibit the formation of pathogenic Alzheimer’s proteins like Aβ in neuronal cells. We herein provided the possibility that the liraglutide-based therapy may be able to reduce such deleterious effects caused by insulin resistance. In view of the beneficial effects of liraglutide administration, these findings suggest that the use of liraglutide may be a promising therapy for AD with insulin-resistant condition. Full article
(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 2.0)
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18 pages, 3692 KiB  
Article
Sequential Transcriptome Changes in the Penumbra after Ischemic Stroke
by In-Ae Choi, Ji Hee Yun, Ji-Hye Kim, Hahn Young Kim, Dong-Hee Choi and Jongmin Lee
Int. J. Mol. Sci. 2019, 20(24), 6349; https://doi.org/10.3390/ijms20246349 - 16 Dec 2019
Cited by 15 | Viewed by 3851
Abstract
To investigate the changes in the expression of specific genes that occur during the acute-to-chronic post-stroke phase, we identified differentially expressed genes (DEGs) between naive cortical tissues and peri-infarct tissues at 1, 4, and 8 weeks after photothrombotic stroke. The profiles of DEGs [...] Read more.
To investigate the changes in the expression of specific genes that occur during the acute-to-chronic post-stroke phase, we identified differentially expressed genes (DEGs) between naive cortical tissues and peri-infarct tissues at 1, 4, and 8 weeks after photothrombotic stroke. The profiles of DEGs were subjected to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and gene ontology analyses, followed by string analysis of the protein–protein interactions (PPI) of the products of these genes. We found 3771, 536, and 533 DEGs at 1, 4, and 8 weeks after stroke, respectively. A marked decrease in biological–process categories, such as brain development and memory, and a decrease in neurotransmitter synaptic and signaling pathways were observed 1 week after stroke. The PPI analysis showed the downregulation of Dlg4, Bdnf, Gria1, Rhoa, Mapk8, and glutamatergic receptors. An increase in biological–process categories, including cell population proliferation, cell adhesion, and inflammatory responses, was detected at 4 and 8 weeks post-stroke. The KEGG pathways of complement and coagulation cascades, phagosomes, antigen processing, and antigen presentation were also altered. CD44, C1, Fcgr2b, Spp1, and Cd74 occupied a prominent position in network analyses. These time-dependent changes in gene profiles reveal the unique pathophysiological characteristics of stroke and suggest new therapeutic targets for this disease. Full article
(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 2.0)
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13 pages, 2648 KiB  
Article
Zinc Binding to Tau Influences Aggregation Kinetics and Oligomer Distribution
by Guilherme G. Moreira, Joana S. Cristóvão, Vukosava M. Torres, Ana P. Carapeto, Mário S. Rodrigues, Isabelle Landrieu, Carlos Cordeiro and Cláudio M. Gomes
Int. J. Mol. Sci. 2019, 20(23), 5979; https://doi.org/10.3390/ijms20235979 - 27 Nov 2019
Cited by 20 | Viewed by 5717
Abstract
Metal ions are well known modulators of protein aggregation and are key players in Alzheimer’s Disease, being found to be associated to pathologic protein deposits in diseased brains. Therefore, understanding how metals influence amyloid aggregation is critical in establishing molecular mechanisms that underlie [...] Read more.
Metal ions are well known modulators of protein aggregation and are key players in Alzheimer’s Disease, being found to be associated to pathologic protein deposits in diseased brains. Therefore, understanding how metals influence amyloid aggregation is critical in establishing molecular mechanisms that underlie disease onset and progression. Here, we report data on the interaction of full-length human Tau protein with calcium and zinc ions, evidencing that Tau self-assembly is differently regulated, depending on the type of bound metal ion. We established that Tau binds 4 Zn2+ and 1 Ca2+ per monomer while using native mass spectrometry analysis, without inducing order or substantial conformational changes in the intrinsically disordered Tau, as determined by structural analysis using circular dichroism and Attenuated Total Reflectance-Fourier Transform Infrared (ATR-FTIR) spectroscopies. However, Tau aggregation is found to proceed differently in the calcium- and -zinc bound forms. While the rate of aggregation, as determined from thioflavin-T (ThT) fluorescence kinetics, is highly increased in both cases, the reaction proceeds via different mechanisms, as evidenced by the absence of the lag phase in the reaction of zinc-bound Tau. Monitoring Tau aggregation using native mass spectrometry indeed evidenced a distinct distribution of Tau conformers along the reaction, as confirmed by dynamic light scattering analysis. We propose that such differences arise from zinc binding at distinct locations within the Tau sequence that prompt both the rapid formation of seeding oligomers through interactions at high affinity sites within the repeat domains, as well as amorphous aggregation, through low affinity interactions with residues elsewhere in the sequence, including at the fuzzy coat domain. Full article
(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 2.0)
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17 pages, 2723 KiB  
Article
Reduced Cholinergic Activity in the Hippocampus of Hippocampal Cholinergic Neurostimulating Peptide Precursor Protein Knockout Mice
by Yuta Madokoro, Yuta Yoshino, Daisuke Kato, Toyohiro Sato, Masayuki Mizuno, Tetsuko Kanamori, Masamitsu Shimazawa, Hideki Hida, Hideaki Hara, Mari Yoshida, Cesario V. Borlongan, Kosei Ojika and Noriyuki Matsukawa
Int. J. Mol. Sci. 2019, 20(21), 5367; https://doi.org/10.3390/ijms20215367 - 28 Oct 2019
Cited by 7 | Viewed by 2996
Abstract
The cholinergic efferent network from the medial septal nucleus to the hippocampus has an important role in learning and memory processes. This cholinergic projection can generate theta oscillations in the hippocampus to efficiently encode novel information. Hippocampal cholinergic neurostimulating peptide (HCNP) induces acetylcholine [...] Read more.
The cholinergic efferent network from the medial septal nucleus to the hippocampus has an important role in learning and memory processes. This cholinergic projection can generate theta oscillations in the hippocampus to efficiently encode novel information. Hippocampal cholinergic neurostimulating peptide (HCNP) induces acetylcholine synthesis in medial septal nuclei. HCNP is processed from the N-terminal region of a 186 amino acid, 21 kD HCNP precursor protein called HCNP-pp (also known as Raf kinase inhibitory protein (RKIP) and phosphatidylethanolamine-binding protein 1 (PEBP1)). In this study, we generated HCNP-pp knockout (KO) mice and assessed their cholinergic septo-hippocampal projection, local field potentials in CA1, and behavioral phenotypes. No significant behavioral phenotype was observed in HCNP-pp KO mice. However, theta power in the CA1 of HCNP-pp KO mice was significantly reduced because of fewer cholineacetyltransferase-positive axons in the CA1 stratum oriens. These observations indicated disruption of cholinergic activity in the septo-hippocampal network. Our study demonstrates that HCNP may be a cholinergic regulator in the septo-hippocampal network. Full article
(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 2.0)
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Review

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15 pages, 1444 KiB  
Review
Gut–Brain Axis as a Pathological and Therapeutic Target for Neurodegenerative Disorders
by Alma Rosa Lezama Toledo, Germán Rivera Monroy, Felipe Esparza Salazar, Jea-Young Lee, Shalini Jain, Hariom Yadav and Cesario Venturina Borlongan
Int. J. Mol. Sci. 2022, 23(3), 1184; https://doi.org/10.3390/ijms23031184 - 21 Jan 2022
Cited by 34 | Viewed by 6643
Abstract
Human lifestyle and dietary behaviors contribute to disease onset and progression. Neurodegenerative diseases (NDDs), considered multifactorial disorders, have been associated with changes in the gut microbiome. NDDs display pathologies that alter brain functions with a tendency to worsen over time. NDDs are a [...] Read more.
Human lifestyle and dietary behaviors contribute to disease onset and progression. Neurodegenerative diseases (NDDs), considered multifactorial disorders, have been associated with changes in the gut microbiome. NDDs display pathologies that alter brain functions with a tendency to worsen over time. NDDs are a worldwide health problem; in the US alone, 12 million Americans will suffer from NDDs by 2030. While etiology may vary, the gut microbiome serves as a key element underlying NDD development and prognosis. In particular, an inflammation-associated microbiome plagues NDDs. Conversely, sequestration of this inflammatory microbiome by a correction in the dysbiotic state of the gut may render therapeutic effects on NDDs. To this end, treatment with short-chain fatty acid-producing bacteria, the main metabolites responsible for maintaining gut homeostasis, ameliorates the inflammatory microbiome. This intimate pathological link between the gut and NDDs suggests that the gut-brain axis (GBA) acts as an underexplored area for developing therapies for NDDs. Traditionally, the classification of NDDs depends on their clinical presentation, mostly manifesting as extrapyramidal and pyramidal movement disorders, with neuropathological evaluation at autopsy as the gold standard for diagnosis. In this review, we highlight the evolving notion that GBA stands as an equally sensitive pathological marker of NDDs, particularly in Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and chronic stroke. Additionally, GBA represents a potent therapeutic target for treating NDDs. Full article
(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 2.0)
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27 pages, 1757 KiB  
Review
Therapeutic Potential of Human Stem Cell Implantation in Alzheimer’s Disease
by Hau Jun Chan, Yanshree, Jaydeep Roy, George Lim Tipoe, Man-Lung Fung and Lee Wei Lim
Int. J. Mol. Sci. 2021, 22(18), 10151; https://doi.org/10.3390/ijms221810151 - 21 Sep 2021
Cited by 17 | Viewed by 5936
Abstract
Alzheimer’s disease (AD) is a progressive debilitating neurodegenerative disease and the most common form of dementia in the older population. At present, there is no definitive effective treatment for AD. Therefore, researchers are now looking at stem cell therapy as a possible treatment [...] Read more.
Alzheimer’s disease (AD) is a progressive debilitating neurodegenerative disease and the most common form of dementia in the older population. At present, there is no definitive effective treatment for AD. Therefore, researchers are now looking at stem cell therapy as a possible treatment for AD, but whether stem cells are safe and effective in humans is still not clear. In this narrative review, we discuss both preclinical studies and clinical trials on the therapeutic potential of human stem cells in AD. Preclinical studies have successfully differentiated stem cells into neurons in vitro, indicating the potential viability of stem cell therapy in neurodegenerative diseases. Preclinical studies have also shown that stem cell therapy is safe and effective in improving cognitive performance in animal models, as demonstrated in the Morris water maze test and novel object recognition test. Although few clinical trials have been completed and many trials are still in phase I and II, the initial results confirm the outcomes of the preclinical studies. However, limitations like rejection, tumorigenicity, and ethical issues are still barriers to the advancement of stem cell therapy. In conclusion, the use of stem cells in the treatment of AD shows promise in terms of effectiveness and safety. Full article
(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 2.0)
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17 pages, 2070 KiB  
Review
Regulation of Melatonin and Neurotransmission in Alzheimer’s Disease
by Jaydeep Roy, Ka Chun Tsui, Jonah Ng, Man-Lung Fung and Lee Wei Lim
Int. J. Mol. Sci. 2021, 22(13), 6841; https://doi.org/10.3390/ijms22136841 - 25 Jun 2021
Cited by 30 | Viewed by 5893
Abstract
Alzheimer’s disease is a neurodegenerative disorder associated with age, and is characterized by pathological markers such as amyloid-beta plaques and neurofibrillary tangles. Symptoms of AD include cognitive impairments, anxiety and depression. It has also been shown that individuals with AD have impaired neurotransmission, [...] Read more.
Alzheimer’s disease is a neurodegenerative disorder associated with age, and is characterized by pathological markers such as amyloid-beta plaques and neurofibrillary tangles. Symptoms of AD include cognitive impairments, anxiety and depression. It has also been shown that individuals with AD have impaired neurotransmission, which may result from the accumulation of amyloid plaques and neurofibrillary tangles. Preclinical studies showed that melatonin, a monoaminergic neurotransmitter released from the pineal gland, is able to ameliorate AD pathologies and restore cognitive impairments. Theoretically, inhibition of the pathological progression of AD by melatonin treatment should also restore the impaired neurotransmission. This review aims to explore the impact of AD on neurotransmission, and whether and how melatonin can enhance neurotransmission via improving AD pathology. Full article
(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 2.0)
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44 pages, 5324 KiB  
Review
Activation of Nrf2 by Natural Bioactive Compounds: A Promising Approach for Stroke?
by Agnese Gugliandolo, Placido Bramanti and Emanuela Mazzon
Int. J. Mol. Sci. 2020, 21(14), 4875; https://doi.org/10.3390/ijms21144875 - 10 Jul 2020
Cited by 42 | Viewed by 4905
Abstract
Stroke represents one of the main causes of disability and death worldwide. The pathological subtypes of stroke are ischemic stroke, the most frequent, and hemorrhagic stroke. Nrf2 is a transcription factor that regulates redox homeostasis. In stress conditions, Nrf2 translocates inside the nucleus [...] Read more.
Stroke represents one of the main causes of disability and death worldwide. The pathological subtypes of stroke are ischemic stroke, the most frequent, and hemorrhagic stroke. Nrf2 is a transcription factor that regulates redox homeostasis. In stress conditions, Nrf2 translocates inside the nucleus and induces the transcription of enzymes involved in counteracting oxidative stress, endobiotic and xenobiotic metabolism, regulators of inflammation, and others. Different natural compounds, including food and plant-derived components, were shown to be able to activate Nrf2, mediating an antioxidant response. Some of these compounds were tested in stroke experimental models showing several beneficial actions. In this review, we focused on the studies that evidenced the positive effects of natural bioactive compounds in stroke experimental models through the activation of Nrf2 pathway. Interestingly, different natural compounds can activate Nrf2 through multiple pathways, inducing a strong antioxidant response associated with the beneficial effects against stroke. According to several studies, the combination of different bioactive compounds can lead to a better neuroprotection. In conclusion, natural bioactive compounds may represent new therapeutic strategies against stroke. Full article
(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 2.0)
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10 pages, 576 KiB  
Review
Bone Marrow-Derived NCS-01 Cells Advance a Novel Cell-Based Therapy for Stroke
by John Brown, You Jeong Park, Jea-Young Lee, Thomas N. Chase, Minako Koga and Cesar V. Borlongan
Int. J. Mol. Sci. 2020, 21(8), 2845; https://doi.org/10.3390/ijms21082845 - 19 Apr 2020
Cited by 9 | Viewed by 3206
Abstract
Human mesenchymal stem cells have been explored for their application in cell-based therapies targeting stroke. Identifying cell lines that stand as safe, accessible, and effective for transplantation, while optimizing dosage, timing, and method of delivery remain critical translational steps towards clinical trials. Preclinical [...] Read more.
Human mesenchymal stem cells have been explored for their application in cell-based therapies targeting stroke. Identifying cell lines that stand as safe, accessible, and effective for transplantation, while optimizing dosage, timing, and method of delivery remain critical translational steps towards clinical trials. Preclinical studies using bone marrow-derived NCS-01 cells show the cells’ ability to confer functional recovery in ischemic stroke. Coculturing primary rat cortical cells or human neural progenitor cells with NCS-01 cells protects against oxygen-glucose deprivation. In the rodent middle cerebral artery occlusion model, intracarotid artery administration of NCS-01 cells demonstrate greater efficacy than other mesenchymal stem cells (MSCs) at improving motor and neurological function, as well as reducing infarct volume and peri-infarct cell loss. NCS-01 cells secrete therapeutic factors, including basic fibroblast growth factor and interleukin-6, while also demonstrating a potentially novel mechanism of extending filopodia towards the site of injury. In this review, we discuss recent preclinical advancements using in vitro and in vivo ischemia models that support the transplantation of NCS-01 in human stroke trials. These results, coupled with the recommendations put forth by the consortium of Stem cell Therapeutics as an Emerging Paradigm for Stroke (STEPS), highlight a framework for conducting preclinical research with the ultimate goal of initiating clinical trials. Full article
(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 2.0)
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Brief Report
High Mobility Group A1 Regulates Transcription Levels of Oligodendrocyte Marker Genes in Cultured Oligodendrocyte Precursor Cells
by Naohiro Egawa, Gen Hamanaka, Kelly K. Chung, Hidehiro Ishikawa, Akihiro Shindo, Takakuni Maki, Ryosuke Takahashi, Haruhisa Inoue, Eng H. Lo and Ken Arai
Int. J. Mol. Sci. 2022, 23(4), 2236; https://doi.org/10.3390/ijms23042236 - 17 Feb 2022
Cited by 2 | Viewed by 1924
Abstract
Oligodendrocyte precursor cells (OPCs) serve as progenitor cells of terminally differentiated oligodendrocytes. Past studies have confirmed the importance of epigenetic system in OPC differentiation to oligodendrocytes. High mobility group A1 (HMGA1) is a small non-histone nuclear protein that binds DNA and modifies the [...] Read more.
Oligodendrocyte precursor cells (OPCs) serve as progenitor cells of terminally differentiated oligodendrocytes. Past studies have confirmed the importance of epigenetic system in OPC differentiation to oligodendrocytes. High mobility group A1 (HMGA1) is a small non-histone nuclear protein that binds DNA and modifies the chromatin conformational state. However, it is still completely unknown about the roles of HMGA1 in the process of OPC differentiation. In this study, we prepared primary OPC cultures from the neonatal rat cortex and examined whether the loss- and gain-of-function of HMGA1 would change the mRNA levels of oligodendrocyte markers, such as Cnp, Mbp, Myrf and Plp during the process of OPC differentiation. In our system, the mRNA levels of Cnp, Mbp, Myrf and Plp increased depending on the oligodendrocyte maturation step, but the level of Hmga1 mRNA decreased. When HMGA1 was knocked down by a siRNA approach, the mRNA levels of Cnp, Mbp, Myrf and Plp were smaller in OPCs with Hmga1 siRNA compared to the ones in the control OPCs. On the contrary, when HMGA1 expression was increased by transfection of the Hmga1 plasmid, the mRNA levels of Cnp, Mbp, Myrf and Plp were slightly larger compared to the ones in the control OPCs. These data may suggest that HMGA1 participates in the process of OPC differentiation by regulating the mRNA expression level of myelin-related genes. Full article
(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 2.0)
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