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Challenges and Innovation in Neurodegenerative Diseases

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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: 30 May 2024 | Viewed by 8220

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Dr. King-Ho Cheung

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Guest Editor

School of Chinese Medicine, Hong Kong Baptist University, Hong Kong 999077, China
Interests: ion channels; electrophysiology; epithelial transport; Alzheimer's disease; neurodegenerative diseases; new drug development

Special Issue Information

Dear Colleagues,

The umbrella of neurodegeneration covers a group of heterogeneous diseases including Alzheimer's disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and others that account for more than 5% of the global burden of all diseases. Although considerable advances in understanding the triggers of neurodegenerative diseases had led to the development of new drugs, there are a handful of challenges that remain in the field that we must overcome to allow cures for the diseases. For example, good disease models that more faithfully recapitulate human disease are devastatingly needed. A full understanding of the involvement of protein aggregation in disease progression and the identification of disease-specific biomarkers would allow the early detection of neurodegeneration and permit reliable disease progression monitoring. The recent application of machine learning and artificial intelligence in new drug discovery and development from natural products as well as the use of stem cell therapy also brings hope to patients with neurodegenerative diseases.

This Special Issue aims to collect views on the current challenges in the field, the exciting progress in deciphering the disease pathogenesis, and the cutting-edge technologies for the early detection of neurodegeneration. The accumulation of innovative findings in these areas may pave the way for the development of therapeutic interventions for neurogenerative diseases.

Dr. King-Ho Cheung
Guest Editor

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Keywords

neurodegenerative diseases
pathogenesis
biomarkers
disease model
natural product
new drug discovery
therapy
machine learning
stem cell therapy

Published Papers (6 papers)

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Research

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15 pages, 3582 KiB

Open AccessArticle

Structurally and Morphologically Distinct Pathological Tau Assemblies Differentially Affect GVB Accumulation

by Marta Jorge-Oliva, Jan R. T. van Weering and Wiep Scheper

Int. J. Mol. Sci. 2023, 24(13), 10865; https://doi.org/10.3390/ijms241310865 - 29 Jun 2023

Cited by 1 | Viewed by 949

Abstract

Tau aggregation is central to the pathogenesis of a large group of neurodegenerative diseases termed tauopathies, but it is still unclear in which way neurons respond to tau pathology and how tau accumulation leads to neurodegeneration. A striking neuron-specific response to tau pathology is presented by granulovacuolar degeneration bodies (GVBs), lysosomal structures that accumulate specific cargo in a dense core. Here we employed different tau aggregation models in primary neurons to investigate which properties of pathological tau assemblies affect GVB accumulation using a combination of confocal microscopy, transmission electron microscopy, and quantitative automated high-content microscopy. Employing GFP-tagged and untagged tau variants that spontaneously form intraneuronal aggregates, we induced pathological tau assemblies with a distinct subcellular localization, morphology, and ultrastructure depending on the presence or absence of the GFP tag. The quantification of the GVB load in the different models showed that an increased GVB accumulation is associated with the untagged tau aggregation model, characterized by shorter and more randomly distributed tau filaments in the neuronal soma. Our data indicate that tau aggregate structure and/or subcellular localization may be key determinants of GVB accumulation. Full article

(This article belongs to the Special Issue Challenges and Innovation in Neurodegenerative Diseases)

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16 pages, 2658 KiB

Open AccessArticle

Altered Tau Kinase Activity in rTg4510 Mice after a Single Interfaced CHIMERA Traumatic Brain Injury

by Wai Hang Cheng, Honor Cheung, Amy Kang, Jianjia Fan, Jennifer Cooper, Mehwish Anwer, Carlos Barron, Anna Wilkinson, Grace Hu, Jefferey Yue, Peter A. Cripton, David J. Vocadlo and Cheryl L. Wellington

Int. J. Mol. Sci. 2023, 24(11), 9439; https://doi.org/10.3390/ijms24119439 - 29 May 2023

Viewed by 1395

Abstract

Traumatic brain injury (TBI) is an established risk factor for neurodegenerative diseases. In this study, we used the Closed Head Injury Model of Engineered Rotational Acceleration (CHIMERA) to investigate the effects of a single high-energy TBI in rTg4510 mice, a mouse model of tauopathy. Fifteen male rTg4510 mice (4 mo) were impacted at 4.0 J using interfaced CHIMERA and were compared to sham controls. Immediately after injury, the TBI mice showed significant mortality (7/15; 47%) and a prolonged duration of loss of the righting reflex. At 2 mo post-injury, surviving mice displayed significant microgliosis (Iba1) and axonal injury (Neurosilver). Western blotting indicated a reduced p-GSK-3β (S9):GSK-3β ratio in TBI mice, suggesting chronic activation of tau kinase. Although longitudinal analysis of plasma total tau suggested that TBI accelerates the appearance of tau in the circulation, there were no significant differences in brain total or p-tau levels, nor did we observe evidence of enhanced neurodegeneration in TBI mice compared to sham mice. In summary, we showed that a single high-energy head impact induces chronic white matter injury and altered GSK-3β activity without an apparent change in post-injury tauopathy in rTg4510 mice. Full article

(This article belongs to the Special Issue Challenges and Innovation in Neurodegenerative Diseases)

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Review

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13 pages, 606 KiB

Open AccessReview

Nervonic Acid Synthesis Substrates as Essential Components in Profiled Lipid Supplementation for More Effective Central Nervous System Regeneration

by Magdalena Namiecinska, Paweł Piatek and Przemysław Lewkowicz

Int. J. Mol. Sci. 2024, 25(7), 3792; https://doi.org/10.3390/ijms25073792 - 28 Mar 2024

Viewed by 440

Abstract

Central nervous system (CNS) damage leads to severe neurological dysfunction as a result of neuronal cell death and axonal degeneration. As, in the mature CNS, neurons have little ability to regenerate their axons and reconstruct neural loss, demyelination is one of the hallmarks of neurological disorders such as multiple sclerosis (MS). Unfortunately, remyelination, as a regenerative process, is often insufficient to prevent axonal loss and improve neurological deficits after demyelination. Currently, there are still no effective therapeutic tools to restore neurological function, but interestingly, emerging studies prove the beneficial effects of lipid supplementation in a wide variety of pathological processes in the human body. In the future, available lipids with a proven beneficial effect on CNS regeneration could be included in supportive therapy, but this topic still requires further studies. Based on our and others’ research, we review the role of exogenous lipids, pointing to substrates that are crucial in the remyelination process but are omitted in available studies, justifying the properly profiled supply of lipids in the human diet as a supportive therapy during CNS regeneration. Full article

(This article belongs to the Special Issue Challenges and Innovation in Neurodegenerative Diseases)

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13 pages, 958 KiB

Open AccessReview

Hypoxia Sensing and Responses in Parkinson’s Disease

by Johannes Burtscher, Yves Duderstadt, Hannes Gatterer, Martin Burtscher, Roman Vozdek, Grégoire P. Millet, Andrew A. Hicks, Hannelore Ehrenreich and Martin Kopp

Int. J. Mol. Sci. 2024, 25(3), 1759; https://doi.org/10.3390/ijms25031759 - 01 Feb 2024

Viewed by 1094

Abstract

Parkinson’s disease (PD) is associated with various deficits in sensing and responding to reductions in oxygen availability (hypoxia). Here we summarize the evidence pointing to a central role of hypoxia in PD, discuss the relation of hypoxia and oxygen dependence with pathological hallmarks of PD, including mitochondrial dysfunction, dopaminergic vulnerability, and alpha-synuclein-related pathology, and highlight the link with cellular and systemic oxygen sensing. We describe cases suggesting that hypoxia may trigger Parkinsonian symptoms but also emphasize that the endogenous systems that protect from hypoxia can be harnessed to protect from PD. Finally, we provide examples of preclinical and clinical research substantiating this potential. Full article

(This article belongs to the Special Issue Challenges and Innovation in Neurodegenerative Diseases)

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29 pages, 2484 KiB

Open AccessReview

Control Theory and Systems Biology: Potential Applications in Neurodegeneration and Search for Therapeutic Targets

by Andrea Angarita-Rodríguez, Yeimy González-Giraldo, Juan J. Rubio-Mesa, Andrés Felipe Aristizábal, Andrés Pinzón and Janneth González

Int. J. Mol. Sci. 2024, 25(1), 365; https://doi.org/10.3390/ijms25010365 - 27 Dec 2023

Viewed by 1212

Abstract

Control theory, a well-established discipline in engineering and mathematics, has found novel applications in systems biology. This interdisciplinary approach leverages the principles of feedback control and regulation to gain insights into the complex dynamics of cellular and molecular networks underlying chronic diseases, including neurodegeneration. By modeling and analyzing these intricate systems, control theory provides a framework to understand the pathophysiology and identify potential therapeutic targets. Therefore, this review examines the most widely used control methods in conjunction with genomic-scale metabolic models in the steady state of the multi-omics type. According to our research, this approach involves integrating experimental data, mathematical modeling, and computational analyses to simulate and control complex biological systems. In this review, we find that the most significant application of this methodology is associated with cancer, leaving a lack of knowledge in neurodegenerative models. However, this methodology, mainly associated with the Minimal Dominant Set (MDS), has provided a starting point for identifying therapeutic targets for drug development and personalized treatment strategies, paving the way for more effective therapies. Full article

(This article belongs to the Special Issue Challenges and Innovation in Neurodegenerative Diseases)

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33 pages, 2200 KiB

Open AccessReview

Exploring the Potential of Aptamers in Targeting Neuroinflammation and Neurodegenerative Disorders: Opportunities and Challenges

by Anna Hau-Yee Kong, Aston Jiaxi Wu, Olivia Ka-Yi Ho, Maggie Ming-Ki Leung, Alexis Shiying Huang, Yuanyuan Yu, Ge Zhang, Aiping Lyu, Min Li and King-Ho Cheung

Int. J. Mol. Sci. 2023, 24(14), 11780; https://doi.org/10.3390/ijms241411780 - 22 Jul 2023

Cited by 2 | Viewed by 2017

Abstract

Neuroinflammation is the precursor for several neurodegenerative diseases (NDDs), such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS). Targeting neuroinflammation has emerged as a promising strategy to address a wide range of CNS pathologies. These NDDs still present significant challenges in terms of limited and ineffective diagnosis and treatment options, driving the need to explore innovative and novel therapeutic alternatives. Aptamers are single-stranded nucleic acids that offer the potential for addressing these challenges through diagnostic and therapeutic applications. In this review, we summarize diagnostic and therapeutic aptamers for inflammatory biomolecules, as well as the inflammatory cells in NDDs. We also discussed the potential of short nucleotides for Aptamer-Based Targeted Brain Delivery through their unique features and modifications, as well as their ability to penetrate the blood-brain barrier. Moreover, the unprecedented opportunities and substantial challenges of using aptamers as therapeutic agents, such as drug efficacy, safety considerations, and pharmacokinetics, are also discussed. Taken together, this review assesses the potential of aptamers as a pioneering approach for target delivery to the CNS and the treatment of neuroinflammation and NDDs. Full article

(This article belongs to the Special Issue Challenges and Innovation in Neurodegenerative Diseases)

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