International Journal of Molecular Sciences

Research

12 pages, 2063 KiB

Open AccessArticle

Blood–Brain Barrier Dysfunction and Aβ42/40 Ratio Dose-Dependent Modulation with the ApoE Genotype within the ATN Framework

by Sofia Toniolo, Francesco Di Lorenzo, Sergio Bernardini, Nicola Biagio Mercuri and Giulia Maria Sancesario

Int. J. Mol. Sci. 2023, 24(15), 12151; https://doi.org/10.3390/ijms241512151 - 29 Jul 2023

Cited by 3 | Viewed by 1287

Abstract

The definition of Alzheimer’s disease (AD) now considers the presence of the markers of amyloid (A), tau deposition (T), and neurodegeneration (N) essential for diagnosis. AD patients have been reported to have increased blood–brain barrier (BBB) dysfunction, but that has not been tested [...] Read more.

The definition of Alzheimer’s disease (AD) now considers the presence of the markers of amyloid (A), tau deposition (T), and neurodegeneration (N) essential for diagnosis. AD patients have been reported to have increased blood–brain barrier (BBB) dysfunction, but that has not been tested within the ATN framework so far. As the field is moving towards the use of blood-based biomarkers, the relationship between BBB disruption and AD-specific biomarkers requires considerable attention. Moreover, other factors have been previously implicated in modulating BBB permeability, including age, gender, and ApoE status. A total of 172 cognitively impaired individuals underwent cerebrospinal fluid (CSF) analysis for AD biomarkers, and data on BBB dysfunction, demographics, and ApoE status were collected. Our data showed that there was no difference in BBB dysfunction across different ATN subtypes, and that BBB damage was not correlated with cognitive impairment. However, patients with BBB disruption, if measured with a high Qalb, had low Aβ40 levels. ApoE status did not affect BBB function but had a dose-dependent effect on the Aβ42/40 ratio. These results might highlight the importance of understanding dynamic changes across the BBB in future studies in patients with AD. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 3.0)

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9 pages, 1354 KiB

Open AccessCommunication

Probing Gut Participation in Parkinson’s Disease Pathology and Treatment via Stem Cell Therapy

by Jea-Young Lee, Vanessa Castelli, Paul R. Sanberg and Cesar V. Borlongan

Int. J. Mol. Sci. 2023, 24(13), 10600; https://doi.org/10.3390/ijms241310600 - 25 Jun 2023

Cited by 1 | Viewed by 1729

Abstract

Accumulating evidence suggests the critical role of the gut–brain axis (GBA) in Parkinson’s disease (PD) pathology and treatment. Recently, stem cell transplantation in transgenic PD mice further implicated the GBA’s contribution to the therapeutic effects of transplanted stem cells. In particular, intravenous transplantation [...] Read more.

Accumulating evidence suggests the critical role of the gut–brain axis (GBA) in Parkinson’s disease (PD) pathology and treatment. Recently, stem cell transplantation in transgenic PD mice further implicated the GBA’s contribution to the therapeutic effects of transplanted stem cells. In particular, intravenous transplantation of human umbilical-cord-blood-derived stem/progenitor cells and plasma reduced motor deficits, improved nigral dopaminergic neuronal survival, and dampened α-synuclein and inflammatory-relevant microbiota and cytokines in both the gut and brain of mouse and rat PD models. That the gut robustly responded to intravenously transplanted stem cells and prompted us to examine in the present study whether direct cell implantation into the gut of transgenic PD mice would enhance the therapeutic effects of stem cells. Contrary to our hypothesis, results revealed that intragut transplantation of stem cells exacerbated motor and gut motility deficits that corresponded with the aggravated expression of inflammatory microbiota, cytokines, and α-synuclein in both the gut and brain of transgenic PD mice. These results suggest that, while the GBA stands as a major source of inflammation in PD, targeting the gut directly for stem cell transplantation may not improve, but may even worsen, functional outcomes, likely due to the invasive approach exacerbating the already inflamed gut. The minimally invasive intravenous transplantation, which likely avoided worsening the inflammatory response of the gut, appears to be a more optimal cell delivery route to ameliorate PD symptoms. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 3.0)

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16 pages, 5541 KiB

Open AccessArticle

Ultrastructural and Molecular Investigation on Peripheral Leukocytes in Alzheimer’s Disease Patients

by Roberta Giannelli, Paola Canale, Renata Del Carratore, Alessandra Falleni, Margherita Bernardeschi, Francesca Forini, Elisa Biagi, Olivia Curzio and Paolo Bongioanni

Int. J. Mol. Sci. 2023, 24(9), 7909; https://doi.org/10.3390/ijms24097909 - 26 Apr 2023

Cited by 2 | Viewed by 2066

Abstract

Thriving literature underlines white blood cell involvement in the inflammatory processes of Alzheimer’s Disease (AD). Among leukocytes, lymphocytes have been considered sentinels of neuroinflammation for years, but recent findings highlighted the pivotal role of neutrophils. Since neutrophils that infiltrate the brain through the [...] Read more.

Thriving literature underlines white blood cell involvement in the inflammatory processes of Alzheimer’s Disease (AD). Among leukocytes, lymphocytes have been considered sentinels of neuroinflammation for years, but recent findings highlighted the pivotal role of neutrophils. Since neutrophils that infiltrate the brain through the brain vascular vessels may affect the immune function of microglia in the brain, a close investigation of the interaction between these cells is important in understanding neuroinflammatory phenomena and the immunological aftermaths that follow. This study aimed to observe how peripheral leukocyte features change at different stages of AD to identify potential molecular markers when the first features of pathological neurodegeneration arise. For this purpose, the examined patients were divided into Mild Cognitive Impairment (MCI) and severely impaired patients (DAT) based on their Cognitive Dementia Rating (CDR). The evaluation of the neutrophil-to-lymphocytes ratio and the morphology and function of leukocytes showed a close relationship between the ultrastructural and the molecular features in AD progression and suggested putative markers for the early stages of the disease. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 3.0)

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10 pages, 1688 KiB

Open AccessArticle

Intrathecal versus Peripheral Inflammatory Protein Profile in MS Patients at Diagnosis: A Comprehensive Investigation on Serum and CSF

by Francesco Pezzini, Annalisa Pisani, Valentina Mazziotti, Damiano Marastoni, Agnese Tamanti, Edilio Borroni, Stefano Magon, Bastian Zinnhardt, Roberta Magliozzi and Massimiliano Calabrese

Int. J. Mol. Sci. 2023, 24(4), 3768; https://doi.org/10.3390/ijms24043768 - 13 Feb 2023

Cited by 4 | Viewed by 2065

Abstract

Intrathecal inflammation plays a key role in the pathogenesis of multiple sclerosis (MS). To better elucidate its relationship with peripheral inflammation, we investigated the correlation between cerebrospinal fluid (CSF) and serum levels of 61 inflammatory proteins. Paired CSF and serum samples were collected [...] Read more.

Intrathecal inflammation plays a key role in the pathogenesis of multiple sclerosis (MS). To better elucidate its relationship with peripheral inflammation, we investigated the correlation between cerebrospinal fluid (CSF) and serum levels of 61 inflammatory proteins. Paired CSF and serum samples were collected from 143 treatment-naïve MS patients at diagnosis. A customized panel of 61 inflammatory molecules was analyzed by a multiplex immunoassay. Correlations between serum and CSF expression levels for each molecule were performed by Spearman’s method. The expression of sixteen CSF proteins correlated with their serum expression (p-value < 0.001): only five molecules (CXCL9, sTNFR2, IFNα2, Pentraxin-3, and TSLP) showed a Rho value >0.40, suggesting moderate CSF/serum correlation. No correlation between inflammatory serum patterns and Q_alb was observed. Correlation analysis of serum expression levels of these sixteen proteins with clinical and MRI parameters pinpointed a subset of five molecules (CXCL9, sTNFR2, IFNα2, IFNβ, and TSLP) negatively correlating with spinal cord lesion volume. However, following FDR correction, only the correlation of CXCL9 remained significant. Our data support the hypothesis that the intrathecal inflammation in MS only partially associates with the peripheral one, except for the expression of some immunomodulators that might have a key role in the initial MS immune response. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 3.0)

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16 pages, 3128 KiB

Open AccessArticle

Alterations to Cerebral Perfusion, Metabolite Profiles, and Neuronal Morphology in the Hippocampus and Cortex of Male and Female Mice during Chronic Exposure to a High-Salt Diet

by Anja Meissner, Alba M. Garcia-Serrano, Lotte Vanherle, Zeinab Rafiee, Nicholas Don-Doncow, Cecilia Skoug, Sara Larsson, Michael Gottschalk, Martin Magnusson and João M. N. Duarte

Int. J. Mol. Sci. 2023, 24(1), 300; https://doi.org/10.3390/ijms24010300 - 24 Dec 2022

Cited by 5 | Viewed by 2241

Abstract

Excess dietary salt reduces resting cerebral blood flow (CBF) and vascular reactivity, which can limit the fueling of neuronal metabolism. It is hitherto unknown whether metabolic derangements induced by high-salt-diet (HSD) exposure during adulthood are reversed by reducing salt intake. In this study, [...] Read more.

Excess dietary salt reduces resting cerebral blood flow (CBF) and vascular reactivity, which can limit the fueling of neuronal metabolism. It is hitherto unknown whether metabolic derangements induced by high-salt-diet (HSD) exposure during adulthood are reversed by reducing salt intake. In this study, male and female mice were fed an HSD from 9 to 16 months of age, followed by a normal-salt diet (ND) thereafter until 23 months of age. Controls were continuously fed either ND or HSD. CBF and metabolite profiles were determined longitudinally by arterial spin labeling magnetic resonance imaging and magnetic resonance spectroscopy, respectively. HSD reduced cortical and hippocampal CBF, which recovered after dietary salt normalization, and affected hippocampal but not cortical metabolite profiles. Compared to ND, HSD increased hippocampal glutamine and phosphocreatine levels and decreased creatine and choline levels. Dietary reversal only allowed recovery of glutamine levels. Histology analyses revealed that HSD reduced the dendritic arborization and spine density of cortical and hippocampal neurons, which were not recovered after dietary salt normalization. We conclude that sustained HSD exposure throughout adulthood causes permanent structural and metabolic alterations to the mouse brain that are not fully normalized by lowering dietary salt during aging. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 3.0)

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11 pages, 1911 KiB

Open AccessArticle

Dysregulated Expression of Transposable Elements in TDP-43^M337V Human Motor Neurons That Recapitulate Amyotrophic Lateral Sclerosis In Vitro

by Braulio Valdebenito-Maturana, Matias Ignacio Rojas-Tapia, Mónica Carrasco and Juan Carlos Tapia

Int. J. Mol. Sci. 2022, 23(24), 16222; https://doi.org/10.3390/ijms232416222 - 19 Dec 2022

Cited by 2 | Viewed by 2127

Abstract

Amyotrophic lateral sclerosis (ALS) is a disease that progressively annihilates spinal cord motor neurons, causing severe motor decline and death. The disease is divided into familial and sporadic ALS. Mutations in the TAR DNA binding protein 43 (TDP-43) have been involved in the [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a disease that progressively annihilates spinal cord motor neurons, causing severe motor decline and death. The disease is divided into familial and sporadic ALS. Mutations in the TAR DNA binding protein 43 (TDP-43) have been involved in the pathological emergence and progression of ALS, although the molecular mechanisms eliciting the disease are unknown. Transposable elements (TEs) and DNA sequences capable of transposing within the genome become dysregulated and transcribed in the presence of TDP-43 mutations. We performed RNA-Seq in human motor neurons (iMNs) derived from induced pluripotent stem cells (iPSCs) from TDP-43 wild-type—iMNs-TDP-43^WT—and mutant—iMNs-TDP-43^M337V—genotypes at 7 and 14 DIV, and, with state-of-the-art bioinformatic tools, analyzed whether TDP-43^M337V alters both gene expression and TE activity. Our results show that TDP-43^M337V induced global changes in the gene expression and TEs levels at all in vitro stages studied. Interestingly, many genetic pathways overlapped with that of the TEs activity, suggesting that TEs control the expression of several genes. TEs correlated with genes that played key roles in the extracellular matrix and RNA processing: all the regulatory pathways affected in ALS. Thus, the loss of TE regulation is present in TDP-43 mutations and is a critical determinant of the disease in human motor neurons. Overall, our results support the evidence that indicates TEs are critical regulatory sequences contributing to ALS neurodegeneration. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 3.0)

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18 pages, 2572 KiB

Open AccessArticle

Red Cell Microparticles Suppress Hematoma Growth Following Intracerebral Hemorrhage in Chronic Nicotine-Exposed Rats

by Ashish K. Rehni, Sunjoo Cho, Zhexuan Zhang, Priyanka Khushal, Ami P. Raval, Sebastian Koch, Miguel A. Perez-Pinzon, Weizhao Zhao, Wenche Jy and Kunjan R. Dave

Int. J. Mol. Sci. 2022, 23(23), 15167; https://doi.org/10.3390/ijms232315167 - 2 Dec 2022

Cited by 1 | Viewed by 1731

Abstract

Spontaneous intracerebral hemorrhage (sICH) is a disabling stroke sub-type, and tobacco use is a prominent risk factor for sICH. We showed that chronic nicotine exposure enhances bleeding post-sICH. Reduction of hematoma growth is a promising effective therapy for sICH in smoking subjects. Red-blood-cell-derived [...] Read more.

Spontaneous intracerebral hemorrhage (sICH) is a disabling stroke sub-type, and tobacco use is a prominent risk factor for sICH. We showed that chronic nicotine exposure enhances bleeding post-sICH. Reduction of hematoma growth is a promising effective therapy for sICH in smoking subjects. Red-blood-cell-derived microparticles (RMPs) are hemostatic agents that limit hematoma expansion following sICH in naïve rats. Considering the importance of testing the efficacy of experimental drugs in animal models with a risk factor for a disease, we tested RMP efficacy and the therapeutic time window in limiting hematoma growth post-sICH in rats exposed to nicotine. Young rats were chronically treated with nicotine using osmotic pumps. sICH was induced in rats using an injection of collagenase in the right striatum. Vehicle/RMPs were administered intravenously. Hematoma volume and neurological impairment were quantified ≈24 h after sICH. Hematoma volumes in male and female nicotine-exposed rats that were treated with RMPs at 2 h post-sICH were significantly lower by 26 and 31% when compared to their respective control groups. RMP therapy was able to limit hematoma volume when administered up to 4.5 h post-sICH in animals of both sexes. Therefore, RMPs may limit hematoma growth in sICH patients exposed to tobacco use. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 3.0)

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10 pages, 1815 KiB

Open AccessArticle

Spatial Memory Training Counteracts Hippocampal GIRK Channel Decrease in the Transgenic APP_Sw,Ind J9 Alzheimer’s Disease Mouse Model

by Sara Temprano-Carazo, Ana Contreras, Carlos A. Saura, Juan D. Navarro-López and Lydia Jiménez-Díaz

Int. J. Mol. Sci. 2022, 23(21), 13444; https://doi.org/10.3390/ijms232113444 - 3 Nov 2022

Cited by 3 | Viewed by 1677

Abstract

G-protein-gated inwardly rectifying potassium (GIRK) channels are critical determinants of neuronal excitability. They have been proposed as potential targets to restore excitatory/inhibitory balance in acute amyloidosis models, where hyperexcitability is a hallmark. However, the role of GIRK signaling in transgenic mice models of [...] Read more.

G-protein-gated inwardly rectifying potassium (GIRK) channels are critical determinants of neuronal excitability. They have been proposed as potential targets to restore excitatory/inhibitory balance in acute amyloidosis models, where hyperexcitability is a hallmark. However, the role of GIRK signaling in transgenic mice models of Alzheimer’s disease (AD) is largely unknown. Here, we study whether progressive amyloid-β (Aβ) accumulation in the hippocampus during aging alters GIRK channel expression in mutant β-amyloid precursor protein (APP_Sw,Ind J9) transgenic AD mice. Additionally, we examine the impact of spatial memory training in a hippocampal-dependent task, on protein expression of GIRK subunits and Regulator of G-protein signaling 7 (RGS7) in the hippocampus of APP_Sw,Ind J9 mice. Firstly, we found a reduction in GIRK2 expression (the main neuronal GIRK channels subunit) in the hippocampus of 6-month-old APP_Sw,Ind J9 mice. Moreover, we found an aging effect on GIRK2 and GIRK3 subunits in both wild type (WT) and APP_Sw,Ind J9 mice. Finally, when 6-month-old animals were challenged to a spatial memory training, GIRK2 expression in the APP_Sw,Ind J9 mice were normalized to WT levels. Together, our results support the evidence that GIRK2 could account for the excitatory/inhibitory neurotransmission imbalance found in AD models, and training in a cognitive hippocampal dependent task may have therapeutic benefits of reversing this effect and lessen early AD deficits. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 3.0)

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19 pages, 5150 KiB

Open AccessArticle

Blockage of KHSRP-NLRP3 by MCC950 Can Reverse the Effect of Manganese-Induced Neuroinflammation in N2a Cells and Rat Brain

by Sharad Singh, Ibrahim Ahmed Shaikh, Sunil S. More, Mater H. Mahnashi, Hailah M. Almohaimeed, Mohamed El-Sherbiny, Mohammed M. Ghoneim, Ahmad Umar, Harshit Kumar Soni, Himanshu Agrawal, Basheer Ahmed Mannasaheb, Aejaz Abdullatif Khan, Uday M. Muddapur and S. M. Shakeel Iqubal

Int. J. Mol. Sci. 2022, 23(21), 13224; https://doi.org/10.3390/ijms232113224 - 30 Oct 2022

Cited by 7 | Viewed by 2912

Abstract

Manganese neurotoxicity has been reported to cause a neurodegenerative disease known as parkinsonism. Previous reports have shown that the expression of the KH-type splicing regulatory protein (KHSRP), a nucleic acid-binding protein, and NLRP3 is increased upon Mn exposure. However, the relation between these [...] Read more.

Manganese neurotoxicity has been reported to cause a neurodegenerative disease known as parkinsonism. Previous reports have shown that the expression of the KH-type splicing regulatory protein (KHSRP), a nucleic acid-binding protein, and NLRP3 is increased upon Mn exposure. However, the relation between these two during Mn toxicity has not been fully deduced. The mouse neuroblastoma (N2a) and SD rats are treated with LPS and MnCl₂ to evaluate the expression of KHSRP and NLRP3. Further, the effect of the NLRP3 inhibitor MCC950 is checked on the expression of NLRP3, KHSRP and pro-inflammatory markers (TNFα, IL-18 and IL-1β) as well as the caspase-1 enzyme. Our results demonstrated an increment in NLRP3 and KHSRP expression post-MnCl₂ exposure in N2a cells and rat brain, while on the other hand with LPS exposure only NLRP3 expression levels were elevated and KHSRP was found to be unaffected. An increased expression of KHSRP, NLRP3, pro-inflammatory markers and the caspase-1 enzyme was observed to be inhibited with MCC950 treatment in MnCl₂-exposed cells and rats. Manganese exposure induces NLRP3 and KHSRP expression to induce neuroinflammation, suggesting a correlation between both which functions in toxicity-related pathways. Furthermore, MCC950 treatment reversed the role of KHSRP from anti-inflammatory to pro-inflammatory. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 3.0)

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20 pages, 2596 KiB

Open AccessArticle

Bi-Allelic Mutations in Zebrafish pank2 Gene Lead to Testicular Atrophy and Perturbed Behavior without Signs of Neurodegeneration

by Luca Mignani, Daniela Zizioli, Deepak Khatri, Nicola Facchinello, Marco Schiavone, Giuseppe De Palma and Dario Finazzi

Int. J. Mol. Sci. 2022, 23(21), 12914; https://doi.org/10.3390/ijms232112914 - 26 Oct 2022

Cited by 3 | Viewed by 1806

Abstract

Coenzyme A (CoA) is an essential cofactor in all living organisms, being involved in a large number of chemical reactions. Sequence variations in pantothenate kinase 2 (PANK2), the first enzyme of CoA biosynthesis, are found in patients affected by Pantothenate Kinase Associated Neurodegeneration [...] Read more.

Coenzyme A (CoA) is an essential cofactor in all living organisms, being involved in a large number of chemical reactions. Sequence variations in pantothenate kinase 2 (PANK2), the first enzyme of CoA biosynthesis, are found in patients affected by Pantothenate Kinase Associated Neurodegeneration (PKAN), one of the most common forms of neurodegeneration, with brain iron accumulation. Knowledge about the biochemical and molecular features of this disorder has increased a lot in recent years. Nonetheless, the main culprit of the pathology is not well defined, and no treatment option is available yet. In order to contribute to the understanding of this disease and facilitate the search for therapies, we explored the potential of the zebrafish animal model and generated lines carrying biallelic mutations in the pank2 gene. The phenotypic characterization of pank2-mutant embryos revealed anomalies in the development of venous vascular structures and germ cells. Adult fish showed testicular atrophy and altered behavioral response in an anxiety test but no evident signs of neurodegeneration. The study suggests that selected cell and tissue types show a higher vulnerability to pank2 deficiency in zebrafish. Deciphering the biological basis of this phenomenon could provide relevant clues for better understanding and treating PKAN. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 3.0)

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Review

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19 pages, 355 KiB

Open AccessReview

Identifying the Target Traumatic Brain Injury Population for Hyperbaric Oxygen Therapy

by Samantha Schimmel, Bassel El Sayed, Gavin Lockard, Jonah Gordon, Isabella Young, Francesco D’Egidio, Jea Young Lee, Thomas Rodriguez and Cesar V. Borlongan

Int. J. Mol. Sci. 2023, 24(19), 14612; https://doi.org/10.3390/ijms241914612 - 27 Sep 2023

Cited by 4 | Viewed by 2332

Abstract

Traumatic brain injury (TBI) results from direct penetrating and indirect non-penetrating forces that alters brain functions, affecting millions of individuals annually. Primary injury following TBI is exacerbated by secondary brain injury; foremost is the deleterious inflammatory response. One therapeutic intervention being increasingly explored [...] Read more.

Traumatic brain injury (TBI) results from direct penetrating and indirect non-penetrating forces that alters brain functions, affecting millions of individuals annually. Primary injury following TBI is exacerbated by secondary brain injury; foremost is the deleterious inflammatory response. One therapeutic intervention being increasingly explored for TBI is hyperbaric oxygen therapy (HBOT), which is already approved clinically for treating open wounds. HBOT consists of 100% oxygen administration, usually between 1.5 and 3 atm and has been found to increase brain oxygenation levels after hypoxia in addition to decreasing levels of inflammation, apoptosis, intracranial pressure, and edema, reducing subsequent secondary injury. The following review examines recent preclinical and clinical studies on HBOT in the context of TBI with a focus on contributing mechanisms and clinical potential. Several preclinical studies have identified pathways, such as TLR4/NF-kB, that are affected by HBOT and contribute to its therapeutic effect. Thus far, the mechanisms mediating HBOT treatment have yet to be fully elucidated and are of interest to researchers. Nonetheless, multiple clinical studies presented in this review have examined the safety of HBOT and demonstrated the improved neurological function of TBI patients after HBOT, deeming it a promising avenue for treatment. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 3.0)

16 pages, 1692 KiB

Open AccessReview

A Brief Review on the Potential of Psychedelics for Treating Alzheimer’s Disease and Related Depression

by Alexander Pilozzi, Simmie Foster, David Mischoulon, Maurizio Fava and Xudong Huang

Int. J. Mol. Sci. 2023, 24(15), 12513; https://doi.org/10.3390/ijms241512513 - 7 Aug 2023

Cited by 3 | Viewed by 7247

Abstract

Alzheimer’s disease (AD), the most common form of senile dementia, is poised to place an even greater societal and healthcare burden as the population ages. With few treatment options for the symptomatic relief of the disease and its unknown etiopathology, more research into [...] Read more.

Alzheimer’s disease (AD), the most common form of senile dementia, is poised to place an even greater societal and healthcare burden as the population ages. With few treatment options for the symptomatic relief of the disease and its unknown etiopathology, more research into AD is urgently needed. Psychedelic drugs target AD-related psychological pathology and symptoms such as depression. Using microdosing, psychedelic drugs may prove to help combat this devastating disease by eliciting psychiatric benefits via acting through various mechanisms of action such as serotonin and dopamine pathways. Herein, we review the studied benefits of a few psychedelic compounds that may show promise in treating AD and attenuating its related depressive symptoms. We used the listed keywords to search through PubMed for relevant preclinical, clinical research, and review articles. The putative mechanism of action (MOA) for psychedelics is that they act mainly as serotonin receptor agonists and induce potential beneficial effects for treating AD and related depression. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 3.0)

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26 pages, 4514 KiB

Open AccessReview

Are Therapies That Target α-Synuclein Effective at Halting Parkinson’s Disease Progression? A Systematic Review

by Abbie T. Rodger, Maryam ALNasser and Wayne G. Carter

Int. J. Mol. Sci. 2023, 24(13), 11022; https://doi.org/10.3390/ijms241311022 - 3 Jul 2023

Cited by 11 | Viewed by 3557

Abstract

There are currently no pharmacological treatments available that completely halt or reverse the progression of Parkinson’s Disease (PD). Hence, there is an unmet need for neuroprotective therapies. Lewy bodies are a neuropathological hallmark of PD and contain aggregated α-synuclein (α-syn) which is thought [...] Read more.

There are currently no pharmacological treatments available that completely halt or reverse the progression of Parkinson’s Disease (PD). Hence, there is an unmet need for neuroprotective therapies. Lewy bodies are a neuropathological hallmark of PD and contain aggregated α-synuclein (α-syn) which is thought to be neurotoxic and therefore a suitable target for therapeutic interventions. To investigate this further, a systematic review was undertaken to evaluate whether anti-α-syn therapies are effective at preventing PD progression in preclinical in vivo models of PD and via current human clinical trials. An electronic literature search was performed using MEDLINE and EMBASE (Ovid), PubMed, the Web of Science Core Collection, and Cochrane databases to collate clinical evidence that investigated the targeting of α-syn. Novel preclinical anti-α-syn therapeutics provided a significant reduction of α-syn aggregations. Biochemical and immunohistochemical analysis of rodent brain tissue demonstrated that treatments reduced α-syn-associated pathology and rescued dopaminergic neuronal loss. Some of the clinical studies did not provide endpoints since they had not yet been completed or were terminated before completion. Completed clinical trials displayed significant tolerability and efficacy at reducing α-syn in patients with PD with minimal adverse effects. Collectively, this review highlights the capacity of anti-α-syn therapies to reduce the accumulation of α-syn in both preclinical and clinical trials. Hence, there is potential and optimism to target α-syn with further clinical trials to restrict dopaminergic neuronal loss and PD progression and/or provide prophylactic protection to avoid the onset of α-syn-induced PD. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 3.0)

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25 pages, 1228 KiB

Open AccessReview

Pediatric-Onset Epilepsy and Developmental Epileptic Encephalopathies Followed by Early-Onset Parkinsonism

by Carlotta Spagnoli, Carlo Fusco and Francesco Pisani

Int. J. Mol. Sci. 2023, 24(4), 3796; https://doi.org/10.3390/ijms24043796 - 14 Feb 2023

Cited by 3 | Viewed by 3258

Abstract

Genetic early-onset Parkinsonism is unique due to frequent co-occurrence of hyperkinetic movement disorder(s) (MD), or additional neurological of systemic findings, including epilepsy in up to 10–15% of cases. Based on both the classification of Parkinsonism in children proposed by Leuzzi and coworkers and [...] Read more.

Genetic early-onset Parkinsonism is unique due to frequent co-occurrence of hyperkinetic movement disorder(s) (MD), or additional neurological of systemic findings, including epilepsy in up to 10–15% of cases. Based on both the classification of Parkinsonism in children proposed by Leuzzi and coworkers and the 2017 ILAE epilepsies classification, we performed a literature review in PubMed. A few discrete presentations can be identified: Parkinsonism as a late manifestation of complex neurodevelopmental disorders, characterized by developmental and epileptic encephalopathies (DE-EE), with multiple, refractory seizure types and severely abnormal EEG characteristics, with or without preceding hyperkinetic MD; Parkinsonism in the context of syndromic conditions with unspecific reduced seizure threshold in infancy and childhood; neurodegenerative conditions with brain iron accumulation, in which childhood DE-EE is followed by neurodegeneration; and finally, monogenic juvenile Parkinsonism, in which a subset of patients with intellectual disability or developmental delay (ID/DD) develop hypokinetic MD between 10 and 30 years of age, following unspecific, usually well-controlled, childhood epilepsy. This emerging group of genetic conditions leading to epilepsy or DE-EE in childhood followed by juvenile Parkinsonism highlights the need for careful long-term follow-up, especially in the context of ID/DD, in order to readily identify individuals at increased risk of later Parkinsonism. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 3.0)

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13 pages, 1190 KiB

Open AccessReview

Overview of the Role of Vanillin in Neurodegenerative Diseases and Neuropathophysiological Conditions

by Clara Iannuzzi, Maria Liccardo and Ivana Sirangelo

Int. J. Mol. Sci. 2023, 24(3), 1817; https://doi.org/10.3390/ijms24031817 - 17 Jan 2023

Cited by 19 | Viewed by 3468

Abstract

Nowadays, bioactive natural products play key roles in drug development due to their safety profile and strong antioxidant power. Vanillin is a natural phenolic compound found in several vanilla beans and widely used for food, cosmetic, and pharmaceutical products. Besides its industrial applications, [...] Read more.

Nowadays, bioactive natural products play key roles in drug development due to their safety profile and strong antioxidant power. Vanillin is a natural phenolic compound found in several vanilla beans and widely used for food, cosmetic, and pharmaceutical products. Besides its industrial applications, vanillin possesses several beneficial effects for human health, such as antioxidant activity in addition to anti-inflammatory, anti-mutagenic, anti-metastatic, and anti-depressant properties. Moreover, vanillin exhibits neuroprotective effects on multiple neurological disorders and neuropathophysiological conditions. This study reviews the mechanisms of action by which vanillin prevents neuroinflammation and neurodegeneration in vitro and in vivo systems, in order to provide the latest views on the beneficial properties of this molecule in chronic neurodegenerative diseases and neuropathophysiological conditions. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 3.0)

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19 pages, 1070 KiB

Open AccessReview

The Role of the JAK/STAT Signaling Pathway in the Pathogenesis of Alzheimer’s Disease: New Potential Treatment Target

by Marta Rusek, Joanna Smith, Kamel El-Khatib, Kennedy Aikins, Stanisław J. Czuczwar and Ryszard Pluta

Int. J. Mol. Sci. 2023, 24(1), 864; https://doi.org/10.3390/ijms24010864 - 3 Jan 2023

Cited by 36 | Viewed by 7123

Abstract

Alzheimer’s disease is characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. However, emerging evidence suggests that neuroinflammation, mediated notably by activated neuroglial cells, neutrophils, and macrophages, also plays an important role in the pathogenesis of Alzheimer’s disease. Therefore, [...] Read more.

Alzheimer’s disease is characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. However, emerging evidence suggests that neuroinflammation, mediated notably by activated neuroglial cells, neutrophils, and macrophages, also plays an important role in the pathogenesis of Alzheimer’s disease. Therefore, understanding the interplay between the nervous and immune systems might be the key to the prevention or delay of Alzheimer’s disease progression. One of the most important mechanisms determining gliogenic cell fate is the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway that is influenced by the overactivation of microglia and astrocytes. The JAK/STAT signaling pathway is one of the critical factors that promote neuroinflammation in neurodegenerative diseases such as Alzheimer’s disease by initiating innate immunity, orchestrating adaptive immune mechanisms, and finally, constraining neuroinflammatory response. Since a chronic neuroinflammatory environment in the brain is a hallmark of Alzheimer’s disease, understanding the process would allow establishing the underlying role of neuroinflammation, then estimating the prognosis of Alzheimer’s disease development and finding a new potential treatment target. In this review, we highlight the recent advances in the potential role of JAK/STAT signaling in neurological diseases with a focus on discussing future research directions regarding novel therapeutic approaches and predictive biomarkers for Alzheimer’s disease. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 3.0)

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13 pages, 1421 KiB

Open AccessReview

Mediterranean Diet and Parkinson’s Disease

by Marco Bisaglia

Int. J. Mol. Sci. 2023, 24(1), 42; https://doi.org/10.3390/ijms24010042 - 20 Dec 2022

Cited by 23 | Viewed by 5163

Abstract

Parkinson’s disease (PD) is an age-related neurodegenerative disorder, diagnosed on the basis of typical motor disturbances, but also characterized by the presence of non-motor symptoms, such as rapid eye movement (REM)-sleep behavior disorders, olfactory impairment, and constipation, which are often prodromal to the [...] Read more.

Parkinson’s disease (PD) is an age-related neurodegenerative disorder, diagnosed on the basis of typical motor disturbances, but also characterized by the presence of non-motor symptoms, such as rapid eye movement (REM)-sleep behavior disorders, olfactory impairment, and constipation, which are often prodromal to the onset of the disease. PD is often associated with the presence of oxidative brain injury and chronic neuroinflammation, with infiltration and accumulation of peripheral immune cells that have been found in affected brain regions of PD patients. Recently, the role of the gut-brain axis in the pathogenesis of PD is getting more and more attention, and several pieces of evidence indicate alterations in the gut microbiota of PD-affected patients. Diet exerts a central role in defining the microbiota composition and different dietetic patterns can result in a higher or lower abundance of specific bacteria that, in turn, can affect gut permeability and express anti- or pro-inflammatory metabolites. In the present review, the effects of the Mediterranean diet in modulating both PD onset and its progression will be considered with a special focus on the antioxidant and anti-inflammatory properties of this dietetic regimen as well as on its effects on the microbiota composition. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 3.0)

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26 pages, 1379 KiB

Open AccessReview

Advances in NURR1-Regulated Neuroinflammation Associated with Parkinson’s Disease

by Murad Al-Nusaif, Yushan Lin, Tianbai Li, Cheng Cheng and Weidong Le

Int. J. Mol. Sci. 2022, 23(24), 16184; https://doi.org/10.3390/ijms232416184 - 19 Dec 2022

Cited by 7 | Viewed by 3912

Abstract

Neuroinflammation plays a crucial role in the progression of neurodegenerative disorders, particularly Parkinson’s disease (PD). Glial cell activation and subsequent adaptive immune involvement are neuroinflammatory features in familial and idiopathic PD, resulting in the death of dopaminergic neuron cells. An oxidative stress response, [...] Read more.

Neuroinflammation plays a crucial role in the progression of neurodegenerative disorders, particularly Parkinson’s disease (PD). Glial cell activation and subsequent adaptive immune involvement are neuroinflammatory features in familial and idiopathic PD, resulting in the death of dopaminergic neuron cells. An oxidative stress response, inflammatory mediator production, and immune cell recruitment and activation are all hallmarks of this activation, leading to chronic neuroinflammation and progressive neurodegeneration. Several studies in PD patients’ cerebrospinal fluid and peripheral blood revealed alterations in inflammatory markers and immune cell populations that may lead to or exacerbate neuroinflammation and perpetuate the neurodegenerative process. Most of the genes causing PD are also expressed in astrocytes and microglia, converting their neuroprotective role into a pathogenic one and contributing to disease onset and progression. Nuclear receptor-related transcription factor 1 (NURR1) regulates gene expression linked to dopaminergic neuron genesis and functional maintenance. In addition to playing a key role in developing and maintaining neurotransmitter phenotypes in dopaminergic neurons, NURR1 agonists have been shown to reverse behavioral and histological abnormalities in animal PD models. NURR1 protects dopaminergic neurons from inflammation-induced degeneration, specifically attenuating neuronal death by suppressing the expression of inflammatory genes in microglia and astrocytes. This narrative review highlights the inflammatory changes in PD and the advances in NURR1-regulated neuroinflammation associated with PD. Further, we present new evidence that targeting this inflammation with a variety of potential NURR1 target therapy medications can effectively slow the progression of chronic neuroinflammation-induced PD. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 3.0)

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11 pages, 815 KiB

Open AccessReview

Stem Cell Therapy for Sequestration of Traumatic Brain Injury-Induced Inflammation

by Mia C. Borlongan and Susanna Rosi

Int. J. Mol. Sci. 2022, 23(18), 10286; https://doi.org/10.3390/ijms231810286 - 7 Sep 2022

Cited by 6 | Viewed by 3447

Abstract

Traumatic brain injury (TBI) is one of the leading causes of long-term neurological disabilities in the world. TBI is a signature disease for soldiers and veterans, but also affects civilians, including adults and children. Following TBI, the brain resident and immune cells turn [...] Read more.

Traumatic brain injury (TBI) is one of the leading causes of long-term neurological disabilities in the world. TBI is a signature disease for soldiers and veterans, but also affects civilians, including adults and children. Following TBI, the brain resident and immune cells turn into a “reactive” state, characterized by the production of inflammatory mediators that contribute to the development of cognitive deficits. Other injuries to the brain, including radiation exposure, may trigger TBI-like pathology, characterized by inflammation. Currently there are no treatments to prevent or reverse the deleterious consequences of brain trauma. The recognition that TBI predisposes stem cell alterations suggests that stem cell-based therapies stand as a potential treatment for TBI. Here, we discuss the inflamed brain after TBI and radiation injury. We further review the status of stem cells in the inflamed brain and the applications of cell therapy in sequestering inflammation in TBI. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 3.0)

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14 pages, 1466 KiB

Open AccessReview

The Pivotal Role of NF-kB in the Pathogenesis and Therapeutics of Alzheimer’s Disease

by Emily Sun, Aishat Motolani, Leonardo Campos and Tao Lu

Int. J. Mol. Sci. 2022, 23(16), 8972; https://doi.org/10.3390/ijms23168972 - 11 Aug 2022

Cited by 108 | Viewed by 7332

Abstract

Alzheimer’s Disease (AD) is the most common neurodegenerative disease worldwide, with a high prevalence that is expected to double every 20 years. Besides the formation of Aβ plaques and neurofibrillary tangles, neuroinflammation is one the major phenotypes that worsens AD progression. Indeed, the [...] Read more.

Alzheimer’s Disease (AD) is the most common neurodegenerative disease worldwide, with a high prevalence that is expected to double every 20 years. Besides the formation of Aβ plaques and neurofibrillary tangles, neuroinflammation is one the major phenotypes that worsens AD progression. Indeed, the nuclear factor-κB (NF-κB) is a well-established inflammatory transcription factor that fuels neurodegeneration. Thus, in this review, we provide an overview of the NF-κB role in the pathogenesis of AD, including its interaction with various molecular factors in AD mice models, neurons, and glial cells. Some of these cell types and molecules include reactive microglia and astrocytes, β-secretase, APOE, glutamate, miRNA, and tau protein, among others. Due to the multifactorial nature of AD development and the failure of many drugs designed to dampen AD progression, the pursuit of novel targets for AD therapeutics, including the NF-κB signaling pathway, is rising. Herein, we provide a synopsis of the drug development landscape for AD treatment, offering the perspective that NF-κB inhibitors may generate widespread interest in AD research in the future. Ultimately, the additional investigation of compounds and small molecules that target NF-κB signaling and the complete understanding of NF-κB mechanistic activation in different cell types will broaden and provide more therapeutic options for AD patients. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 3.0)

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8 pages, 3499 KiB

Open AccessBrief Report

Striatal-Inoculation of α-Synuclein Preformed Fibrils Aggravated the Phenotypes of REM Sleep without Atonia in A53T BAC-SNCA Transgenic Mice

by Shinya Okuda, Takeo Nakayama, Norihito Uemura, Rie Hikawa, Masashi Ikuno, Hodaka Yamakado, Haruhisa Inoue, Naoko Tachibana, Yu Hayashi, Ryosuke Takahashi and Naohiro Egawa

Int. J. Mol. Sci. 2022, 23(21), 13390; https://doi.org/10.3390/ijms232113390 - 2 Nov 2022

Cited by 3 | Viewed by 2308

Abstract

Accumulation of α-synuclein (α-syn) is the pathological hallmark of α-synucleinopathy. Rapid eye movement (REM) sleep behavior disorder (RBD) is a pivotal manifestation of α-synucleinopathy including Parkinson’s disease (PD). RBD is clinically confirmed by REM sleep without atonia (RWA) in polysomnography. To accurately characterize [...] Read more.

Accumulation of α-synuclein (α-syn) is the pathological hallmark of α-synucleinopathy. Rapid eye movement (REM) sleep behavior disorder (RBD) is a pivotal manifestation of α-synucleinopathy including Parkinson’s disease (PD). RBD is clinically confirmed by REM sleep without atonia (RWA) in polysomnography. To accurately characterize RWA preceding RBD and their underlying α-syn pathology, we inoculated α-syn preformed fibrils (PFFs) into the striatum of A53T human α-syn BAC transgenic (A53T BAC-SNCA Tg) mice which exhibit RBD-like phenotypes with RWA. RWA phenotypes were aggravated by PFFs-inoculation in A53T BAC-SNCA Tg mice at 1 month after inoculation, in which prominent α-syn pathology in the pedunculopontine nucleus (PPN) was observed. The intensity of RWA phenotype could be dependent on the severity of the underlying α-syn pathology. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 3.0)

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9 pages, 1353 KiB

Open AccessBrief Report

Reduced VDAC1, Maintained Mitochondrial Dynamics and Enhanced Mitochondrial Biogenesis in a Transgenic Tau Mouse Model of Alzheimer’s Disease

by Murali Vijayan and P. Hemachandra Reddy

Int. J. Mol. Sci. 2022, 23(15), 8561; https://doi.org/10.3390/ijms23158561 - 2 Aug 2022

Cited by 11 | Viewed by 2547

Abstract

Alzheimer’s disease (AD) is one of the most common forms of neurodegeneration, defined by reduced cognitive function, which is caused by the gradual death of neurons in the brain. Recent studies have shown an age-dependent rise in the levels of voltage-dependent anion channel [...] Read more.

Alzheimer’s disease (AD) is one of the most common forms of neurodegeneration, defined by reduced cognitive function, which is caused by the gradual death of neurons in the brain. Recent studies have shown an age-dependent rise in the levels of voltage-dependent anion channel 1 (VDAC1) in AD. In addition, we discovered an aberrant interaction between VDAC1 and P-TAU in the brains of AD patients, which led to abnormalities in the structural and functional integrity of the mitochondria. The purpose of our study is to understand the protective effects of reduced VDAC1 against impaired mitochondrial dynamics and defective mitochondrial biogenesis in transgenic TAU mice. Recently, we crossed heterozygote VDAC1 knockout (VDAC1^+/−) mice with transgenic TAU mice to obtain double-mutant VDAC1^+/−/TAU mice. Our goal was to evaluate whether a partial decrease in VDAC1 lessens the amount of mitochondrial toxicity in transgenic Tau (P301L) mice. We found that mitochondrial fission proteins were significantly reduced, and mitochondrial fusion and biogenesis proteins were increased in double-mutant mice compared to TAU mice. On the basis of these discoveries, the current work may have significance for the development of reduced-VDAC1-based treatments for individuals suffering from AD as well as other tauopathies. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 3.0)

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