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Neurodegenerative Diseases: Molecular Mechanisms and Therapies, 2nd Edition

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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 (30 August 2024) | Viewed by 15920

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Dr. Zhidong Zhou

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Translational Therapeutics Laboratory, Duke-NUS Graduate Medical School, NBD, Level 6, 8 College Road, Singapore 169857, Singapore
Interests: biomarkers, therapeutic targets and compounds for Parkinson's disease and other neurodegenerative diseases
Special Issues, Collections and Topics in MDPI journals

Dr. Alexandre Hiroaki Kihara

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Guest Editor

Centro de Matemática, Computação e Cognição, Universidade Federal do ABC, São Bernardo do Campo, Brazil
Interests: stem cells; sci; genome; CRISPR associated endonuclease Cas9; gene editing; electrocorticography; high frequency oscillation; seizures
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neurodegenerative diseases are a group of heterogeneous disorders characterized with progressive neuron vulnerability and even neuron demise in the brain or peripheral nervous system, which are listed within the leading causes for human death. Among various neurodegenerative conditions, Alzheimer's disease and Parkinson's disease (PD) are the most common neurodegenerative disorders. With the aging of our population, the prevalence of neurodegenerative diseases increases significantly, posing serious healthy and economic challenges all around the world. Although oxidative stress, protein aggregation, mitochondria impairment, and neuroinflammation are relevant to neurodegeneration, the disease pathogenesis are not fully understood and no therapy available for these degenerative disorders. Recently, cell therapies using human cell derived dopamine neurons to replace lost neurons in PD patient brains show promise and the first human clinical trial of transplantation of induced pluripotent stem cells derived human dopamine progenitors is under investigation in the Center for iPS Cell Research and Application (CiRA), Kyoto University, which brings hopes to patients with PD and other degenerative diseases.

The aim of this Special Issue is to discuss the disease pathogenesis and new therapeutic agents or therapeutic strategies to protect or alleviate neurodegeneration in human neurodegenerative disorders.

Dr. Zhidong Zhou
Dr. Alexandre Hiroaki Kihara
Guest Editors

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Keywords

neurodegeneration
neurodegenerative diseases
protein aggregation
pathogenesis
mitochondria
neuroinflammation
oxidative stress
cell therapy
clinical trial

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Published Papers (9 papers)

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Editorial

Jump to: Research, Review

3 pages, 174 KiB

Open AccessEditorial

Neurodegenerative Diseases: Molecular Mechanisms and Therapies 2nd Edition

by Zhi Dong Zhou and Alexandre Hiroaki Kihara

Int. J. Mol. Sci. 2024, 25(21), 11334; https://doi.org/10.3390/ijms252111334 - 22 Oct 2024

Viewed by 657

Abstract

Neurodegenerative disorders are multiple chronic neurological diseases that pose a serious public health risk to our society, especially among the aging population [...] Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies, 2nd Edition)

Research

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9 pages, 3651 KiB

Open AccessCommunication

Oxysterol Induces Expression of 60 kDa Chaperone Protein on Cell Surface of Microglia

by Koanhoi Kim, Hyok-rae Cho, Bo-young Kim, Jaesung Kim, Dongha Park, Ryuk Jun Kwon and Yonghae Son

Int. J. Mol. Sci. 2024, 25(16), 9073; https://doi.org/10.3390/ijms25169073 - 21 Aug 2024

Viewed by 820

Abstract

Microglia, essential immune cells in the brain, play crucial roles in neuroinflammation by performing various functions such as neurogenesis, synaptic pruning, and pathogen defense. These cells are activated by inflammatory factors like β-amyloid (Aβ) and oxysterols, leading to morphological and functional changes, including the secretion of inflammatory cytokines and the upregulation of MHC class II molecules. This study focused on identifying specific markers for microglial activation, with a particular emphasis on the roles of oxysterols in this process. We used the HMC3 human microglial cell line to investigate the induction of heat shock protein 60 (HSP60), a chaperonin protein by oxysterols, specifically in the presence of 25-hydroxycholesterol (25OHChol) and 27-hydroxycholesterol (27OHChol). Our findings obtained by the proteomics approach revealed that these oxysterols significantly increased HSP60 expression on microglial cells. This induction was further confirmed using Western blot analysis and immunofluorescence microscopy. Additionally, Aβ_1–42 also promoted HSP60 expression, indicating its role as a microglial activator. HSP60 involved in protein folding and immune modulation was identified as a potential marker for microglial activation. This study underscores the importance of HSP60 in the inflammatory response of microglia, suggesting its utility as a target for new therapeutic approaches in neuroinflammatory diseases such as Alzheimer’s disease (AD). Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies, 2nd Edition)

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18 pages, 4018 KiB

Open AccessArticle

Pramipexole Hyperactivates the External Globus Pallidus and Impairs Decision-Making in a Mouse Model of Parkinson’s Disease

by Hisayoshi Kubota, Xinzhu Zhou, Xinjian Zhang, Hirohisa Watanabe and Taku Nagai

Int. J. Mol. Sci. 2024, 25(16), 8849; https://doi.org/10.3390/ijms25168849 - 14 Aug 2024

Viewed by 1938

Abstract

In patients with Parkinson’s disease (PD), dopamine replacement therapy with dopamine D2/D3 receptor agonists induces impairments in decision-making, including pathological gambling. The neurobiological mechanisms underlying these adverse effects remain elusive. Here, in a mouse model of PD, we investigated the effects of the dopamine D3 receptor (D3R)-preferring agonist pramipexole (PPX) on decision-making. PD model mice were generated using a bilateral injection of the toxin 6-hydroxydopamine into the dorsolateral striatum. Subsequent treatment with PPX increased disadvantageous choices characterized by a high-risk/high-reward in the touchscreen-based Iowa Gambling Task. This effect was blocked by treatment with the selective D3R antagonist PG-01037. In model mice treated with PPX, the number of c-Fos-positive cells was increased in the external globus pallidus (GPe), indicating dysregulation of the indirect pathway in the corticothalamic-basal ganglia circuitry. In accordance, chemogenetic inhibition of the GPe restored normal c-Fos activation and rescued PPX-induced disadvantageous choices. These findings demonstrate that the hyperactivation of GPe neurons in the indirect pathway impairs decision-making in PD model mice. The results provide a candidate mechanism and therapeutic target for pathological gambling observed during D2/D3 receptor pharmacotherapy in PD patients. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies, 2nd Edition)

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15 pages, 4368 KiB

Open AccessArticle

Proteomic Analysis of a Rat Streptozotocin Model Shows Dysregulated Biological Pathways Implicated in Alzheimer’s Disease

by Esdras Matheus Gomes da Silva, Juliana S. G. Fischer, Isadora de Lourdes Signorini Souza, Amanda Caroline Camillo Andrade, Leonardo de Castro e Souza, Marcos Kaoann de Andrade, Paulo C. Carvalho, Ricardo Lehtonen Rodrigues Souza, Maria Aparecida Barbato Frazao Vital and Fabio Passetti

Int. J. Mol. Sci. 2024, 25(5), 2772; https://doi.org/10.3390/ijms25052772 - 28 Feb 2024

Cited by 1 | Viewed by 1712

Abstract

Alzheimer’s Disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss and cognitive impairment, affecting 35 million individuals worldwide. Intracerebroventricular (ICV) injection of low to moderate doses of streptozotocin (STZ) in adult male Wistar rats can reproduce classical physiopathological hallmarks of AD. This biological model is known as ICV-STZ. Most studies are focused on the description of behavioral and morphological aspects of the ICV-STZ model. However, knowledge regarding the molecular aspects of the ICV-STZ model is still incipient. Therefore, this work is a first attempt to provide a wide proteome description of the ICV-STZ model based on mass spectrometry (MS). To achieve that, samples from the pre-frontal cortex (PFC) and hippocampus (HPC) of the ICV-STZ model and control (wild-type) were used. Differential protein abundance, pathway, and network analysis were performed based on the protein identification and quantification of the samples. Our analysis revealed dysregulated biological pathways implicated in the early stages of late-onset Alzheimer’s disease (LOAD), based on differentially abundant proteins (DAPs). Some of these DAPs had their mRNA expression further investigated through qRT-PCR. Our results shed light on the AD onset and demonstrate the ICV-STZ as a valid model for LOAD proteome description. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies, 2nd Edition)

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15 pages, 2347 KiB

Open AccessArticle

Beyond Amyloid: A Machine Learning-Driven Approach Reveals Properties of Potent GSK-3β Inhibitors Targeting Neurofibrillary Tangles

by Martin Nwadiugwu, Ikenna Onwuekwe, Echezona Ezeanolue and Hongwen Deng

Int. J. Mol. Sci. 2024, 25(5), 2646; https://doi.org/10.3390/ijms25052646 - 24 Feb 2024

Cited by 1 | Viewed by 1874

Abstract

Current treatments for Alzheimer’s disease (AD) focus on slowing memory and cognitive decline, but none offer curative outcomes. This study aims to explore and curate the common properties of active, drug-like molecules that modulate glycogen synthase kinase 3β (GSK-3β), a well-documented kinase with increased activity in tau hyperphosphorylation and neurofibrillary tangles—hallmarks of AD pathology. Leveraging quantitative structure–activity relationship (QSAR) data from the PubChem and ChEMBL databases, we employed seven machine learning models: logistic regression (LogR), k-nearest neighbors (KNN), random forest (RF), support vector machine (SVM), extreme gradient boosting (XGB), neural networks (NNs), and ensemble majority voting. Our goal was to correctly predict active and inactive compounds that inhibit GSK-3β activity and identify their key properties. Among the six individual models, the NN demonstrated the highest performance with a 79% AUC-ROC on unbalanced external validation data, while the SVM model was superior in accurately classifying the compounds. The SVM and RF models surpassed NN in terms of Kappa values, and the ensemble majority voting model demonstrated slightly better accuracy to the NN on the external validation data. Feature importance analysis revealed that hydrogen bonds, phenol groups, and specific electronic characteristics are important features of molecular descriptors that positively correlate with active GSK-3β inhibition. Conversely, structural features like imidazole rings, sulfides, and methoxy groups showed a negative correlation. Our study highlights the significance of structural, electronic, and physicochemical descriptors in screening active candidates against GSK-3β. These predictive features could prove useful in therapeutic strategies to understand the important properties of GSK-3β candidate inhibitors that may potentially benefit non-amyloid-based AD treatments targeting neurofibrillary tangles. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies, 2nd Edition)

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15 pages, 2088 KiB

Open AccessArticle

New Insights into Endogenous Retrovirus-K Transcripts in Amyotrophic Lateral Sclerosis

by Laura Moreno-Martinez, Sofía Macías-Redondo, Mark Strunk, María Isabel Guillén-Antonini, Christian Lunetta, Claudia Tarlarini, Silvana Penco, Ana Cristina Calvo, Rosario Osta and Jon Schoorlemmer

Int. J. Mol. Sci. 2024, 25(3), 1549; https://doi.org/10.3390/ijms25031549 - 26 Jan 2024

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Abstract

Retroviral reverse transcriptase activity and the increased expression of human endogenous retroviruses (HERVs) are associated with amyotrophic lateral sclerosis (ALS). We were interested in confirming HERVK overexpression in the ALS brain, its use as an accessory diagnostic marker for ALS, and its potential interplay with neuroinflammation. Using qPCR to analyze HERVK expression in peripheral blood mononuclear cells (PBMCs) and in postmortem brain samples from ALS patients, no significant differences were observed between patients and control subjects. By contrast, we report alterations in the expression patterns of specific HERVK copies, especially in the brainstem. Out of 27 HERVK copies sampled, the relative expression of 17 loci was >1.2-fold changed in samples from ALS patients. In particular, the relative expression of two HERVK copies (Chr3-3 and Chr3-5) was significantly different in brainstem samples from ALS patients compared with controls. Further qPCR analysis of inflammation markers in brain samples revealed a significant increase in NLRP3 levels, while TNFA, IL6, and GZMB showed slight decreases. We cannot confirm global HERVK overexpression in ALS, but we can report the ALS-specific overexpression of selected HERVK copies in the ALS brain. Our data are compatible with the requirement for better patient stratification and support the potential importance of particular HERVK copies in ALS. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies, 2nd Edition)

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Review

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19 pages, 1153 KiB

Open AccessReview

Pathology of Amyloid-β (Aβ) Peptide Peripheral Clearance in Alzheimer’s Disease

by Andrey Tsoy, Bauyrzhan Umbayev, Aliya Kassenova, Bibifatima Kaupbayeva and Sholpan Askarova

Int. J. Mol. Sci. 2024, 25(20), 10964; https://doi.org/10.3390/ijms252010964 - 11 Oct 2024

Viewed by 1499

Abstract

Although Alzheimer’s disease (AD) is traditionally viewed as a central nervous system disorder driven by the cerebral accumulation of toxic beta-amyloid (Aβ) peptide, new interpretations of the amyloid cascade hypothesis have led to the recognition of the dynamic equilibrium in which Aβ resides and the importance of peripheral Aβ production and degradation in maintaining healthy Aβ levels. Our review sheds light on the critical role of peripheral organs, particularly the liver, in the metabolism and clearance of circulating Aβ. We explore the mechanisms of Aβ transport across the blood–brain barrier (BBB) via transport proteins such as LRP1 and P-glycoprotein. We also examine how peripheral clearance mechanisms, including enzymatic degradation and phagocytic activity, impact Aβ homeostasis. Our review also discusses potential therapeutic strategies targeting peripheral Aβ clearance pathways. By enhancing these pathways, we propose a novel approach to reducing cerebral Aβ burden, potentially slowing AD progression. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies, 2nd Edition)

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17 pages, 4173 KiB

Open AccessReview

Advances in Therapeutics to Alleviate Cognitive Decline and Neuropsychiatric Symptoms of Alzheimer’s Disease

by Jialin Li, Anita Haj Ebrahimi and Afia B. Ali

Int. J. Mol. Sci. 2024, 25(10), 5169; https://doi.org/10.3390/ijms25105169 - 9 May 2024

Cited by 1 | Viewed by 2595

Abstract

Dementia exists as a ‘progressive clinical syndrome of deteriorating mental function significant enough to interfere with activities of daily living’, with the most prevalent type of dementia being Alzheimer’s disease (AD), accounting for about 80% of diagnosed cases. AD is associated with an increased risk of comorbidity with other clinical conditions such as hypertension, diabetes, and neuropsychiatric symptoms (NPS) including, agitation, anxiety, and depression as well as increased mortality in late life. For example, up to 70% of patients diagnosed with AD are affected by anxiety. As aging is the major risk factor for AD, this represents a huge global burden in ageing populations. Over the last 10 years, significant efforts have been made to recognize the complexity of AD and understand the aetiology and pathophysiology of the disease as well as biomarkers for early detection. Yet, earlier treatment options, including acetylcholinesterase inhibitors and glutamate receptor regulators, have been limited as they work by targeting the symptoms, with only the more recent FDA-approved drugs being designed to target amyloid-β protein with the aim of slowing down the progression of the disease. However, these drugs may only help temporarily, cannot stop or reverse the disease, and do not act by reducing NPS associated with AD. The first-line treatment options for the management of NPS are selective serotonin reuptake inhibitors/selective noradrenaline reuptake inhibitors (SSRIs/SNRIs) targeting the monoaminergic system; however, they are not rational drug choices for the management of anxiety disorders since the GABAergic system has a prominent role in their development. Considering the overall treatment failures and side effects of currently available medication, there is an unmet clinical need for rationally designed therapies for anxiety disorders associated with AD. In this review, we summarize the current status of the therapy of AD and aim to highlight novel angles for future drug therapy in our ongoing efforts to alleviate the cognitive deficits and NPS associated with this devastating disease. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies, 2nd Edition)

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12 pages, 871 KiB

Open AccessReview

History of Parkinson’s Disease-Associated Gene, Parkin: Research over a Quarter Century in Quest of Finding the Physiological Substrate

by Tohru Kitada, Mustafa T. Ardah and M. Emdadul Haque

Int. J. Mol. Sci. 2023, 24(23), 16734; https://doi.org/10.3390/ijms242316734 - 24 Nov 2023

Cited by 4 | Viewed by 2347

Abstract

Parkin, the gene responsible for hereditary Parkinson’s disease (PD) called “Autosomal Recessive Juvenile Parkinsonism (AR-JP)” was discovered a quarter of a century ago. Owing to its huge gene structure and unique protein functions, parkin has become a subject of interest to those involved in PD research and researchers and clinicians in various fields and is being vigorously studied worldwide in relation to its nature and disease. The gene structure was registered under the gene name “parkin” in the GenBank in 1997. In 1998, deletion and point mutations in the parkin gene were reported, thereby demonstrating parkin is the causative gene for hereditary PD. Although 25 years have passed since the gene’s discovery and many researchers have worked tirelessly to elucidate the function of the Parkin protein and the mechanism of its role against neuronal cell death and pathogenesis remain unknown, which raises a major question concerning the current leading hypothesis. In this review, we present the results of related research on the parkin gene in chronological order and discuss unresolved problems concerning its function and pathology as well as new trends in the research conducted to solve them. The relationship between parkin and tumorigenesis has also been addressed from the perspective of Parkin’s redox molecule. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies, 2nd Edition)

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