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New Mechanisms and Therapeutics in Neurological Diseases 3.0

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

Deadline for manuscript submissions: closed (31 July 2024) | Viewed by 13023

Special Issue Editor

Special Issue Information

Dear Colleagues,

The term “neurodegenerative diseases” (NDs) collectively defines a group of pathological conditions of the nervous system characterized by the degeneration of neurons. This group of disorders includes different diseases leading to dementia or motor neuron disfunction, resulting in disability. Among them, Alzheimer’s (AD) and Parkinson’s diseases (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) have the greatest importance because of their devastating outcomes and enormous socio-economic impact. Although they have a variegated etiology, an increasing role in their pathology is ascribed to neuroinflammatory processes. Neuroinflammation may affect not only neurons but also non-neuronal astrocytes and microglia cells, as well as immune cells entering the nervous system. These cells cooperate in both the damage and the repair of diseased brain tissue. Interactions between cells and the extracellular environment have emerged as new targets for the treatment of neurodegenerative disorders. However, the heterogeneity of the molecular and cellular mechanisms underlying these diseases hinders efforts at slowing down the progression of these diseases and their effective treatment. Moreover, the availability of biomarkers with appropriate sensitivity and specificity that could predict treatment success is very limited.

Inflammatory and infectious diseases of the central nervous system (CNS) may also be involved in the pathogenesis of neurodegeneration. Microbial infection has emerged as a new risk factor for NDs, and new evidence supports the universal hypothesis that some bacteria, viruses, and even fungi could be involved not only in brain inflammation but also in neurodegeneration and dementia. The diagnosis of CNS infections and the identification of potential pathogenic pathways of these diseases are also topics of interest for this Special Issue, as well as the therapy and prevention of these diseases, including vaccination.

Studies on malignant primary brain tumors are also welcome. These tumors are a highly heterogeneous group of malignancies, with varied frequency within different age groups. Among them, glioblastoma is the most common and most malignant primary CNS tumor, affecting patients of all ages, from children to adults. Glioblastoma multiforme is an especially fatal tumor type, and only moderate progress has been achieved in its clinical management in recent years.

The goal of this Special Issue is to collect original research manuscripts, short communications, and reviews on the latest advances regarding new mechanisms of and therapeutics for neurological diseases, including neurodegeneration, neuroinflammation, and tumors of the central nervous system.

Topics of interest include (but are not limited to):

  • Biological mechanisms related to neurodegeneration, inflammation, and tumorigenesis within the central nervous system;
  • Neurodegenerative diseases as proteinopathies;
  • Relationship between neurodegeneration and inflammation;
  • New potential biomarkers of Alzheimer’s disease and other neurodegenerative diseases, including mild cognitive impairment, multiple sclerosis, Parkinson’s disease, Lewy body dementia, frontotemporal dementia, amyotrophic lateral sclerosis, Huntington’s disease, and prion diseases;
  • Prognostic value of biomarkers of neurodegeneration in the conversion from mild cognitive impairment to fully symptomatic dementia;
  • Cytokines, chemokines, and matrix metalloproteinases as prognostic factors in the carcinogenesis of CNS malignant tumors;
  • Mediators of inflammation, chemokines, and their receptors as novel tumor markers in malignant tumors of the central nervous system in relation to the histological type of tumors;
  • Relationships between COVID-19 and neurological diseases.

This Special Issue is supervised by Prof. Dr. Barbara Mroczko and assisted by our Topical Advisory Panel Member Dr. Kristina Mlinac-Jerković (University of Zagreb).

Prof. Dr. Barbara Mroczko
Guest Editor

Manuscript Submission Information

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Keywords

  • neurodegeneration
  • neuroinflammation
  • neurodegenerative diseases
  • neurodevelopmental disorders
  • tumor markers
  • specific proteins

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Related Special Issue

Published Papers (9 papers)

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Research

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23 pages, 3870 KiB  
Article
Network Analysis of Enhancer–Promoter Interactions Highlights Cell-Type-Specific Mechanisms of Transcriptional Regulation Variation
by Justin Koesterich, Jiayi Liu, Sarah E. Williams, Nan Yang and Anat Kreimer
Int. J. Mol. Sci. 2024, 25(18), 9840; https://doi.org/10.3390/ijms25189840 - 11 Sep 2024
Viewed by 1035
Abstract
Gene expression is orchestrated by a complex array of gene regulatory elements that govern transcription in a cell-type-specific manner. Though previously studied, the ability to utilize regulatory elements to identify disrupting variants remains largely elusive. To identify important factors within these regions, we [...] Read more.
Gene expression is orchestrated by a complex array of gene regulatory elements that govern transcription in a cell-type-specific manner. Though previously studied, the ability to utilize regulatory elements to identify disrupting variants remains largely elusive. To identify important factors within these regions, we generated enhancer–promoter interaction (EPI) networks and investigated the presence of disease-associated variants that fall within these regions. Our study analyzed six neuronal cell types across neural differentiation, allowing us to examine closely related cell types and across differentiation stages. Our results expand upon previous findings of cell-type specificity of enhancer, promoter, and transcription factor binding sites. Notably, we find that regulatory regions within EPI networks can identify the enrichment of variants associated with neuropsychiatric disorders within specific cell types and network sub-structures. This enrichment within sub-structures can allow for a better understanding of potential mechanisms by which variants may disrupt transcription. Together, our findings suggest that EPIs can be leveraged to better understand cell-type-specific regulatory architecture and used as a selection method for disease-associated variants to be tested in future functional assays. Combined with these future functional characterization assays, EPIs can be used to better identify and characterize regulatory variants’ effects on such networks and model their mechanisms of gene regulation disruption across different disorders. Such findings can be applied in practical settings, such as diagnostic tools and drug development. Full article
(This article belongs to the Special Issue New Mechanisms and Therapeutics in Neurological Diseases 3.0)
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16 pages, 9707 KiB  
Article
Increased Expression of the Neuropeptides PACAP/VIP in the Brain of Mice with CNS Targeted Production of IL-6 Is Mediated in Part by Trans-Signalling
by Alessandro Castorina, Jurgen Scheller, Kevin A. Keay, Rubina Marzagalli, Stefan Rose-John and Iain L. Campbell
Int. J. Mol. Sci. 2024, 25(17), 9453; https://doi.org/10.3390/ijms25179453 - 30 Aug 2024
Viewed by 640
Abstract
Inflammation with expression of interleukin 6 (IL-6) in the central nervous system (CNS) occurs in several neurodegenerative/neuroinflammatory conditions and may cause neurochemical changes to endogenous neuroprotective systems. Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) are two neuropeptides with well-established protective [...] Read more.
Inflammation with expression of interleukin 6 (IL-6) in the central nervous system (CNS) occurs in several neurodegenerative/neuroinflammatory conditions and may cause neurochemical changes to endogenous neuroprotective systems. Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) are two neuropeptides with well-established protective and anti-inflammatory properties. Yet, whether PACAP and VIP levels are altered in mice with CNS-restricted, astrocyte-targeted production of IL-6 (GFAP-IL6) remains unknown. In this study, PACAP/VIP levels were assessed in the brain of GFAP-IL6 mice. In addition, we utilised bi-genic GFAP-IL6 mice carrying the human sgp130-Fc transgene (termed GFAP-IL6/sgp130Fc mice) to determine whether trans-signalling inhibition rescued PACAP/VIP changes in the CNS. Transcripts and protein levels of PACAP and VIP, as well as their receptors PAC1, VPAC1 and VPAC2, were significantly increased in the cerebrum and cerebellum of GFAP-IL6 mice vs. wild type (WT) littermates. These results were paralleled by a robust activation of the JAK/STAT3, NF-κB and ERK1/2MAPK pathways in GFAP-IL6 mice. In contrast, co-expression of sgp130Fc in GFAP-IL6/sgp130Fc mice reduced VIP expression and activation of STAT3 and NF-κB pathways, but it failed to rescue PACAP, PACAP/VIP receptors and Erk1/2MAPK phosphorylation. We conclude that forced expression of IL-6 in astrocytes induces the activation of the PACAP/VIP neuropeptide system in the brain, which is only partly modulated upon IL-6 trans-signalling inhibition. Increased expression of PACAP/VIP neuropeptides and receptors may represent a homeostatic response of the CNS to an uncontrolled IL-6 synthesis and its neuroinflammatory consequences. Full article
(This article belongs to the Special Issue New Mechanisms and Therapeutics in Neurological Diseases 3.0)
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14 pages, 4478 KiB  
Article
Toxic Advanced Glycation End-Products Inhibit Axonal Elongation Mediated by β-Tubulin Aggregation in Mice Optic Nerves
by Hayahide Ooi, Ayako Furukawa, Masayoshi Takeuchi and Yoshiki Koriyama
Int. J. Mol. Sci. 2024, 25(13), 7409; https://doi.org/10.3390/ijms25137409 - 5 Jul 2024
Viewed by 874
Abstract
Advanced glycation end-products (AGEs) form through non-enzymatic glycation of various proteins. Optic nerve degeneration is a frequent complication of diabetes, and retinal AGE accumulation is strongly linked to the development of diabetic retinopathy. Type 2 diabetes mellitus is a major risk factor for [...] Read more.
Advanced glycation end-products (AGEs) form through non-enzymatic glycation of various proteins. Optic nerve degeneration is a frequent complication of diabetes, and retinal AGE accumulation is strongly linked to the development of diabetic retinopathy. Type 2 diabetes mellitus is a major risk factor for Alzheimer’s disease (AD), with patients often exhibiting optic axon degeneration in the nerve fiber layer. Notably, a gap exists in our understanding of how AGEs contribute to neuronal degeneration in the optic nerve within the context of both diabetes and AD. Our previous work demonstrated that glyceraldehyde (GA)-derived toxic advanced glycation end-products (TAGE) disrupt neurite outgrowth through TAGE–β-tubulin aggregation and tau phosphorylation in neural cultures. In this study, we further illustrated GA-induced suppression of optic nerve axonal elongation via abnormal β-tubulin aggregation in mouse retinas. Elucidating this optic nerve degeneration mechanism holds promise for bridging the knowledge gap regarding vision loss associated with diabetes mellitus and AD. Full article
(This article belongs to the Special Issue New Mechanisms and Therapeutics in Neurological Diseases 3.0)
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14 pages, 1192 KiB  
Article
The Relationships between Cerebrospinal Fluid Glial (CXCL12, CX3CL, YKL-40) and Synaptic Biomarkers (Ng, NPTXR) in Early Alzheimer’s Disease
by Agnieszka Kulczyńska-Przybik, Maciej Dulewicz, Julia Doroszkiewicz, Renata Borawska, Agnieszka Słowik, Henrik Zetterberg, Jörg Hanrieder, Kaj Blennow and Barbara Mroczko
Int. J. Mol. Sci. 2023, 24(17), 13166; https://doi.org/10.3390/ijms241713166 - 24 Aug 2023
Cited by 7 | Viewed by 1560
Abstract
In addition to amyloid and tau pathology in the central nervous system (CNS), inflammatory processes and synaptic dysfunction are highly important mechanisms involved in the development and progression of dementia diseases. In the present study, we conducted a comparative analysis of selected pro-inflammatory [...] Read more.
In addition to amyloid and tau pathology in the central nervous system (CNS), inflammatory processes and synaptic dysfunction are highly important mechanisms involved in the development and progression of dementia diseases. In the present study, we conducted a comparative analysis of selected pro-inflammatory proteins in the CNS with proteins reflecting synaptic damage and core biomarkers in mild cognitive impairment (MCI) and early Alzheimer’s disease (AD). To our knowledge, no studies have yet compared CXCL12 and CX3CL1 with markers of synaptic disturbance in cerebrospinal fluid (CSF) in the early stages of dementia. The quantitative assessment of selected proteins in the CSF of patients with MCI, AD, and non-demented controls (CTRL) was performed using immunoassays (single- and multiplex techniques). In this study, increased CSF concentration of CX3CL1 in MCI and AD patients correlated positively with neurogranin (r = 0.74; p < 0.001, and r = 0.40; p = 0.020, respectively), ptau181 (r = 0.49; p = 0.040), and YKL-40 (r = 0.47; p = 0.050) in MCI subjects. In addition, elevated CSF levels of CXCL12 in the AD group were significantly associated with mini-mental state examination score (r = −0.32; p = 0.040). We found significant evidence to support an association between CX3CL1 and neurogranin, already in the early stages of cognitive decline. Furthermore, our findings indicate that CXCL12 might be a useful marker for tract severity of cognitive impairment. Full article
(This article belongs to the Special Issue New Mechanisms and Therapeutics in Neurological Diseases 3.0)
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Review

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37 pages, 3007 KiB  
Review
High Blood Pressure and Impaired Brain Health: Investigating the Neuroprotective Potential of Magnesium
by Khawlah Alateeq, Erin I. Walsh and Nicolas Cherbuin
Int. J. Mol. Sci. 2024, 25(22), 11859; https://doi.org/10.3390/ijms252211859 - 5 Nov 2024
Viewed by 680
Abstract
High blood pressure (BP) is a significant contributor to the disease burden globally and is emerging as an important cause of morbidity and mortality in the young as well as the old. The well-established impact of high BP on neurodegeneration, cognitive impairment, and [...] Read more.
High blood pressure (BP) is a significant contributor to the disease burden globally and is emerging as an important cause of morbidity and mortality in the young as well as the old. The well-established impact of high BP on neurodegeneration, cognitive impairment, and dementia is widely acknowledged. However, the influence of BP across its full range remains unclear. This review aims to explore in more detail the effects of BP levels on neurodegeneration, cognitive function, and dementia. Moreover, given the pressing need to identify strategies to reduce BP levels, particular attention is placed on reviewing the role of magnesium (Mg) in ageing and its capacity to lower BP levels, and therefore potentially promote brain health. Overall, the review aims to provide a comprehensive synthesis of the evidence linking BP, Mg and brain health. It is hoped that these insights will inform the development of cost-effective and scalable interventions to protect brain health in the ageing population. Full article
(This article belongs to the Special Issue New Mechanisms and Therapeutics in Neurological Diseases 3.0)
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15 pages, 522 KiB  
Review
The Role of ACE2 in Neurological Disorders: From Underlying Mechanisms to the Neurological Impact of COVID-19
by Jingwen Li, Xiangrui Kong, Tingting Liu, Meiyan Xian and Jianshe Wei
Int. J. Mol. Sci. 2024, 25(18), 9960; https://doi.org/10.3390/ijms25189960 - 15 Sep 2024
Cited by 1 | Viewed by 896
Abstract
Angiotensin-converting enzyme 2 (ACE2) has become a hot topic in neuroscience research in recent years, especially in the context of the global COVID-19 pandemic, where its role in neurological diseases has received widespread attention. ACE2, as a multifunctional metalloprotease, not only plays a [...] Read more.
Angiotensin-converting enzyme 2 (ACE2) has become a hot topic in neuroscience research in recent years, especially in the context of the global COVID-19 pandemic, where its role in neurological diseases has received widespread attention. ACE2, as a multifunctional metalloprotease, not only plays a critical role in the cardiovascular system but also plays an important role in the protection, development, and inflammation regulation of the nervous system. The COVID-19 pandemic further highlights the importance of ACE2 in the nervous system. SARS-CoV-2 enters host cells by binding to ACE2, which may directly or indirectly affect the nervous system, leading to a range of neurological symptoms. This review aims to explore the function of ACE2 in the nervous system as well as its potential impact and therapeutic potential in various neurological diseases, providing a new perspective for the treatment of neurological disorders. Full article
(This article belongs to the Special Issue New Mechanisms and Therapeutics in Neurological Diseases 3.0)
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29 pages, 942 KiB  
Review
Genetic and Epigenetic Biomarkers Linking Alzheimer’s Disease and Age-Related Macular Degeneration
by Snježana Kaštelan, Tamara Nikuševa-Martić, Daria Pašalić, Antonela Gverović Antunica and Danijela Mrazovac Zimak
Int. J. Mol. Sci. 2024, 25(13), 7271; https://doi.org/10.3390/ijms25137271 - 2 Jul 2024
Viewed by 1361
Abstract
Alzheimer’s disease (AD) represents a prominent neurodegenerative disorder (NDD), accounting for the majority of dementia cases worldwide. In addition to memory deficits, individuals with AD also experience alterations in the visual system. As the retina is an extension of the central nervous system [...] Read more.
Alzheimer’s disease (AD) represents a prominent neurodegenerative disorder (NDD), accounting for the majority of dementia cases worldwide. In addition to memory deficits, individuals with AD also experience alterations in the visual system. As the retina is an extension of the central nervous system (CNS), the loss in retinal ganglion cells manifests clinically as decreased visual acuity, narrowed visual field, and reduced contrast sensitivity. Among the extensively studied retinal disorders, age-related macular degeneration (AMD) shares numerous aging processes and risk factors with NDDs such as cognitive impairment that occurs in AD. Histopathological investigations have revealed similarities in pathological deposits found in the retina and brain of patients with AD and AMD. Cellular aging processes demonstrate similar associations with organelles and signaling pathways in retinal and brain tissues. Despite these similarities, there are distinct genetic backgrounds underlying these diseases. This review comprehensively explores the genetic similarities and differences between AMD and AD. The purpose of this review is to discuss the parallels and differences between AMD and AD in terms of pathophysiology, genetics, and epigenetics. Full article
(This article belongs to the Special Issue New Mechanisms and Therapeutics in Neurological Diseases 3.0)
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25 pages, 1811 KiB  
Review
Extracellular Vesicles as Mediators of Neuroinflammation in Intercellular and Inter-Organ Crosstalk
by Andrea Cabrera-Pastor
Int. J. Mol. Sci. 2024, 25(13), 7041; https://doi.org/10.3390/ijms25137041 - 27 Jun 2024
Cited by 3 | Viewed by 1378
Abstract
Neuroinflammation, crucial in neurological disorders like Alzheimer’s disease, multiple sclerosis, and hepatic encephalopathy, involves complex immune responses. Extracellular vesicles (EVs) play a pivotal role in intercellular and inter-organ communication, influencing disease progression. EVs serve as key mediators in the immune system, containing molecules [...] Read more.
Neuroinflammation, crucial in neurological disorders like Alzheimer’s disease, multiple sclerosis, and hepatic encephalopathy, involves complex immune responses. Extracellular vesicles (EVs) play a pivotal role in intercellular and inter-organ communication, influencing disease progression. EVs serve as key mediators in the immune system, containing molecules capable of activating molecular pathways that exacerbate neuroinflammatory processes in neurological disorders. However, EVs from mesenchymal stem cells show promise in reducing neuroinflammation and cognitive deficits. EVs can cross CNS barriers, and peripheral immune signals can influence brain function via EV-mediated communication, impacting barrier function and neuroinflammatory responses. Understanding EV interactions within the brain and other organs could unveil novel therapeutic targets for neurological disorders. Full article
(This article belongs to the Special Issue New Mechanisms and Therapeutics in Neurological Diseases 3.0)
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26 pages, 1413 KiB  
Review
Common and Trace Metals in Alzheimer’s and Parkinson’s Diseases
by Julia Doroszkiewicz, Jakub Ali Farhan, Jan Mroczko, Izabela Winkel, Maciej Perkowski and Barbara Mroczko
Int. J. Mol. Sci. 2023, 24(21), 15721; https://doi.org/10.3390/ijms242115721 - 29 Oct 2023
Cited by 20 | Viewed by 3749
Abstract
Trace elements and metals play critical roles in the normal functioning of the central nervous system (CNS), and their dysregulation has been implicated in neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). In a healthy CNS, zinc, copper, iron, and [...] Read more.
Trace elements and metals play critical roles in the normal functioning of the central nervous system (CNS), and their dysregulation has been implicated in neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). In a healthy CNS, zinc, copper, iron, and manganese play vital roles as enzyme cofactors, supporting neurotransmission, cellular metabolism, and antioxidant defense. Imbalances in these trace elements can lead to oxidative stress, protein aggregation, and mitochondrial dysfunction, thereby contributing to neurodegeneration. In AD, copper and zinc imbalances are associated with amyloid-beta and tau pathology, impacting cognitive function. PD involves the disruption of iron and manganese levels, leading to oxidative damage and neuronal loss. Toxic metals, like lead and cadmium, impair synaptic transmission and exacerbate neuroinflammation, impacting CNS health. The role of aluminum in AD neurofibrillary tangle formation has also been noted. Understanding the roles of these elements in CNS health and disease might offer potential therapeutic targets for neurodegenerative disorders. The Codex Alimentarius standards concerning the mentioned metals in foods may be one of the key legal contributions to safeguarding public health. Further research is needed to fully comprehend these complex mechanisms and develop effective interventions. Full article
(This article belongs to the Special Issue New Mechanisms and Therapeutics in Neurological Diseases 3.0)
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