International Journal of Molecular Sciences

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Open AccessEditorial

Special Issue ‘Advances in Neurodegenerative Diseases Research and Therapy 2.0’

by Sumonto Mitra

Int. J. Mol. Sci. 2024, 25(9), 4709; https://doi.org/10.3390/ijms25094709 - 26 Apr 2024

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Abstract

Neurodegenerative disorders (NDs) and the development of various therapeutic strategies to combat them have received increased attention in recent decades [...] Full article

(This article belongs to the Special Issue Advances in Neurodegenerative Diseases Research and Therapy 2.0)

Research

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20 pages, 6749 KiB

Open AccessArticle

Transferrin-Conjugated Melittin-Loaded L-Arginine-Coated Iron Oxide Nanoparticles for Mitigating Beta-Amyloid Pathology of the 5XFAD Mouse Brain

by Moonseok Choi, Junghwa Ryu, Huy Duc Vu, Dongsoo Kim, Young-Jin Youn, Min Hui Park, Phuong Tu Huynh, Gyu-Bin Hwang, Sung Won Youn and Yun Ha Jeong

Int. J. Mol. Sci. 2023, 24(19), 14954; https://doi.org/10.3390/ijms241914954 - 6 Oct 2023

Cited by 6 | Viewed by 1929

Abstract

Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases and a major contributor to dementia. Although the cause of this condition has been identified long ago as aberrant aggregations of amyloid and tau proteins, effective therapies for it remain elusive. The [...] Read more.

Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases and a major contributor to dementia. Although the cause of this condition has been identified long ago as aberrant aggregations of amyloid and tau proteins, effective therapies for it remain elusive. The complexities of drug development for AD treatment are often compounded by the impermeable blood–brain barrier and low-yield brain delivery. In addition, the use of high drug concentrations to overcome this challenge may entail side effects. To address these challenges and enhance the precision of delivery into brain regions affected by amyloid aggregation, we proposed a transferrin-conjugated nanoparticle-based drug delivery system. The transferrin-conjugated melittin-loaded L-arginine-coated iron oxide nanoparticles (Tf-MeLioNs) developed in this study successfully mitigated melittin-induced cytotoxicity and hemolysis in the cell culture system. In the 5XFAD mouse brain, Tf-MeLioNs remarkably reduced amyloid plaque accumulation, particularly in the hippocampus. This study suggested Tf-LioNs as a potential drug delivery platform and Tf-MeLioNs as a candidate for therapeutic drug targeting of amyloid plaques in AD. These findings provide a foundation for further exploration and advancement in AD therapeutics. Full article

(This article belongs to the Special Issue Advances in Neurodegenerative Diseases Research and Therapy 2.0)

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18 pages, 3291 KiB

Open AccessArticle

Neuronal Death Caused by HMGB1-Evoked via Inflammasomes from Thrombin-Activated Microglia Cells

by Meei-Ling Sheu, Liang-Yi Pan, Cheng-Ning Yang, Jason Sheehan, Liang-Yu Pan, Weir-Chiang You, Chien-Chia Wang, Hong-Shiu Chen and Hung-Chuan Pan

Int. J. Mol. Sci. 2023, 24(16), 12664; https://doi.org/10.3390/ijms241612664 - 11 Aug 2023

Cited by 4 | Viewed by 1400

Abstract

Microglial cells are a macrophage-like cell type residing within the CNS. These cells evoke pro-inflammatory responses following thrombin-induced brain damage. Inflammasomes, which are large caspase-1-activating protein complexes, play a critical role in mediating the extracellular release of HMGB1 in activated immune cells. The [...] Read more.

Microglial cells are a macrophage-like cell type residing within the CNS. These cells evoke pro-inflammatory responses following thrombin-induced brain damage. Inflammasomes, which are large caspase-1-activating protein complexes, play a critical role in mediating the extracellular release of HMGB1 in activated immune cells. The exact role of inflammasomes in microglia activated by thrombin remains unclear, particularly as it relates to the downstream functions of HMGB1. After receiving microinjections of thrombin, Sprague Dawley rats of 200 to 250 gm were studied in terms of behaviors and immunohistochemical staining. Primary culture of microglia cells and BV-2 cells were used for the assessment of signal pathways. In a water maze test and novel object recognition analysis, microinjections of thrombin impaired rats’ short-term and long-term memory, and such detrimental effects were alleviated by injecting anti-HMGB-1 antibodies. After thrombin microinjections, the increased oxidative stress of neurons was aggravated by HMGB1 injections but attenuated by anti-HMGB-1 antibodies. Such responses occurred in parallel with the volume of activated microglia cells, as well as their expressions of HMGB-1, IL-1β, IL-18, and caspase-I. In primary microglia cells and BV-2 cell lines, thrombin also induced NO release and mRNA expressions of iNOS, IL-1β, IL-18, and activated caspase-I. HMGB-1 aggravated these responses, which were abolished by anti-HMGB-1 antibodies. In conclusion, thrombin induced microglia activation through triggering inflammasomes to release HMGB1, contributing to neuronal death. Such an action was counteracted by the anti-HMGB-1 antibodies. The refinement of HMGB-1 modulated the neuro-inflammatory response, which was attenuated in thrombin-associated neurodegenerative disorder. Full article

(This article belongs to the Special Issue Advances in Neurodegenerative Diseases Research and Therapy 2.0)

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22 pages, 7549 KiB

Open AccessArticle

Exploration of the Shared Molecular Mechanisms between COVID-19 and Neurodegenerative Diseases through Bioinformatic Analysis

by Yingchao Shi, Wenhao Liu, Yang Yang, Yali Ci and Lei Shi

Int. J. Mol. Sci. 2023, 24(5), 4839; https://doi.org/10.3390/ijms24054839 - 2 Mar 2023

Cited by 6 | Viewed by 3031

Abstract

The COVID-19 pandemic has caused millions of deaths and remains a major public health burden worldwide. Previous studies found that a large number of COVID-19 patients and survivors developed neurological symptoms and might be at high risk of neurodegenerative diseases, such as Alzheimer’s [...] Read more.

The COVID-19 pandemic has caused millions of deaths and remains a major public health burden worldwide. Previous studies found that a large number of COVID-19 patients and survivors developed neurological symptoms and might be at high risk of neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). We aimed to explore the shared pathways between COVID-19, AD, and PD by using bioinformatic analysis to reveal potential mechanisms, which may explain the neurological symptoms and degeneration of brain that occur in COVID-19 patients, and to provide early intervention. In this study, gene expression datasets of the frontal cortex were employed to detect common differentially expressed genes (DEGs) of COVID-19, AD, and PD. A total of 52 common DEGs were then examined using functional annotation, protein–protein interaction (PPI) construction, candidate drug identification, and regulatory network analysis. We found that the involvement of the synaptic vesicle cycle and down-regulation of synapses were shared by these three diseases, suggesting that synaptic dysfunction might contribute to the onset and progress of neurodegenerative diseases caused by COVID-19. Five hub genes and one key module were obtained from the PPI network. Moreover, 5 drugs and 42 transcription factors (TFs) were also identified on the datasets. In conclusion, the results of our study provide new insights and directions for follow-up studies of the relationship between COVID-19 and neurodegenerative diseases. The hub genes and potential drugs we identified may provide promising treatment strategies to prevent COVID-19 patients from developing these disorders. Full article

(This article belongs to the Special Issue Advances in Neurodegenerative Diseases Research and Therapy 2.0)

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14 pages, 1365 KiB

Open AccessArticle

The Relationship between Iron and LRRK2 in a 6-OHDA-Induced Parkinson’s Disease Model

by Ruru Jia, Yanling Liu, Ke Shuai, Cheng Zhou, Lei Chen, Li Zhu and Xiao-Mei Wu

Int. J. Mol. Sci. 2023, 24(4), 3709; https://doi.org/10.3390/ijms24043709 - 13 Feb 2023

Cited by 6 | Viewed by 2591

Abstract

The pathogenesis of Parkinson’s disease (PD) is very complex and still needs further exploration. Leucine-rich repeat kinase 2 (LRRK2) is associated with familial PD in mutant forms and sporadic PD in the wild-type form. Abnormal iron accumulation is found in the substantia nigra [...] Read more.

The pathogenesis of Parkinson’s disease (PD) is very complex and still needs further exploration. Leucine-rich repeat kinase 2 (LRRK2) is associated with familial PD in mutant forms and sporadic PD in the wild-type form. Abnormal iron accumulation is found in the substantia nigra of PD patients, but its exact effects are not very clear. Here, we show that iron dextran exacerbates the neurological deficit and loss of dopaminergic neurons in 6-OHDA lesioned rats. 6-OHDA and ferric ammonium citrate (FAC) significantly increase the activity of LRRK2 as reflected by the phosphorylation of LRRK2, at S935 and S1292 sites. 6-OHDA-induced LRRK2 phosphorylation is attenuated by the iron chelator deferoxamine, especially at the S1292 site. 6-OHDA and FAC markedly induce the expression of pro-apoptotic molecules and the production of ROS by activating LRRK2. Furthermore, G2019S-LRRK2 with high kinase activity showed the strongest absorptive capacity for ferrous iron and the highest intracellular iron content among WT-LRRK2, G2019S-LRRK2, and kinase-inactive D2017A-LRRK2 groups. Taken together, our results demonstrate that iron promotes the activation of LRRK2, and active LRRK2 accelerates ferrous iron uptake, suggesting that there exists an interplay between iron and LRRK2 in dopaminergic neurons, providing a new perspective to uncover the underlying mechanisms of PD occurrence. Full article

(This article belongs to the Special Issue Advances in Neurodegenerative Diseases Research and Therapy 2.0)

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15 pages, 43215 KiB

Open AccessArticle

DDC-Promoter-Driven Chemogenetic Activation of SNpc Dopaminergic Neurons Alleviates Parkinsonian Motor Symptoms

by Dong-Chan Seo, Yeon Ha Ju, Jin-Ju Seo, Soo-Jin Oh, C. Justin Lee, Seung Eun Lee and Min-Ho Nam

Int. J. Mol. Sci. 2023, 24(3), 2491; https://doi.org/10.3390/ijms24032491 - 27 Jan 2023

Cited by 2 | Viewed by 2866

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder with typical motor symptoms. Recent studies have suggested that excessive GABA from reactive astrocytes tonically inhibits dopaminergic neurons and reduces the expression of tyrosine hydroxylase (TH), the key dopamine-synthesizing enzyme, in the substantia nigra pars compacta [...] Read more.

Parkinson’s disease (PD) is a neurodegenerative disorder with typical motor symptoms. Recent studies have suggested that excessive GABA from reactive astrocytes tonically inhibits dopaminergic neurons and reduces the expression of tyrosine hydroxylase (TH), the key dopamine-synthesizing enzyme, in the substantia nigra pars compacta (SNpc). However, the expression of DOPA decarboxylase (DDC), another dopamine-synthesizing enzyme, is relatively spared, raising a possibility that the live but non-functional TH-negative/DDC-positive neurons could be the therapeutic target for rescuing PD motor symptoms. However, due to the absence of a validated DDC-specific promoter, manipulating DDC-positive neuronal activity has not been tested as a therapeutic strategy for PD. Here, we developed an AAV vector expressing mCherry under rat DDC promoter (AAV-rDDC-mCherry) and validated the specificity in the rat SNpc. Modifying this vector, we expressed hM3Dq (Gq-DREADD) under DDC promoter in the SNpc and ex vivo electrophysiologically validated the functionality. In the A53T-mutated alpha-synuclein overexpression model of PD, the chemogenetic activation of DDC-positive neurons in the SNpc significantly alleviated the parkinsonian motor symptoms and rescued the nigrostriatal TH expression. Altogether, our DDC-promoter will allow dopaminergic neuron-specific gene delivery in rodents. Furthermore, we propose that the activation of dormant dopaminergic neurons could be a potential therapeutic strategy for PD. Full article

(This article belongs to the Special Issue Advances in Neurodegenerative Diseases Research and Therapy 2.0)

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Open AccessReview

Presenilin: A Multi-Functional Molecule in the Pathogenesis of Alzheimer’s Disease and Other Neurodegenerative Diseases

by Yang Sun, Sadequl Islam, Makoto Michikawa and Kun Zou

Int. J. Mol. Sci. 2024, 25(3), 1757; https://doi.org/10.3390/ijms25031757 - 1 Feb 2024

Cited by 6 | Viewed by 2389

Abstract

Presenilin, a transmembrane protein primarily known for its role in Alzheimer’s disease (AD) as part of the γ-secretase complex, has garnered increased attention due to its multifaceted functions in various cellular processes. Recent investigations have unveiled a plethora of functions beyond its amyloidogenic [...] Read more.

Presenilin, a transmembrane protein primarily known for its role in Alzheimer’s disease (AD) as part of the γ-secretase complex, has garnered increased attention due to its multifaceted functions in various cellular processes. Recent investigations have unveiled a plethora of functions beyond its amyloidogenic role. This review aims to provide a comprehensive overview of presenilin’s diverse roles in AD and other neurodegenerative disorders. It includes a summary of well-known substrates of presenilin, such as its involvement in amyloid precursor protein (APP) processing and Notch signaling, along with other functions. Additionally, it highlights newly discovered functions, such as trafficking function, regulation of ferritin expression, apolipoprotein E (ApoE) secretion, the interaction of ApoE and presenilin, and the Aβ42-to-Aβ40-converting activity of ACE. This updated perspective underscores the evolving landscape of presenilin research, emphasizing its broader impact beyond established pathways. The incorporation of these novel findings accentuates the dynamic nature of presenilin’s involvement in cellular processes, further advancing our comprehension of its multifaceted roles in neurodegenerative disorders. By synthesizing evidence from a range of studies, this review sheds light on the intricate web of presenilin functions and their implications in health and disease. Full article

(This article belongs to the Special Issue Advances in Neurodegenerative Diseases Research and Therapy 2.0)

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31 pages, 6997 KiB

Open AccessReview

Physical Exercise as Disease-Modifying Alternative against Alzheimer’s Disease: A Gut–Muscle–Brain Partnership

by Debora Cutuli, Davide Decandia, Giacomo Giacovazzo and Roberto Coccurello

Int. J. Mol. Sci. 2023, 24(19), 14686; https://doi.org/10.3390/ijms241914686 - 28 Sep 2023

Cited by 6 | Viewed by 4001

Abstract

Alzheimer’s disease (AD) is a common cause of dementia characterized by neurodegenerative dysregulations, cognitive impairments, and neuropsychiatric symptoms. Physical exercise (PE) has emerged as a powerful tool for reducing chronic inflammation, improving overall health, and preventing cognitive decline. The connection between the immune [...] Read more.

Alzheimer’s disease (AD) is a common cause of dementia characterized by neurodegenerative dysregulations, cognitive impairments, and neuropsychiatric symptoms. Physical exercise (PE) has emerged as a powerful tool for reducing chronic inflammation, improving overall health, and preventing cognitive decline. The connection between the immune system, gut microbiota (GM), and neuroinflammation highlights the role of the gut–brain axis in maintaining brain health and preventing neurodegenerative diseases. Neglected so far, PE has beneficial effects on microbial composition and diversity, thus providing the potential to alleviate neurological symptoms. There is bidirectional communication between the gut and muscle, with GM diversity modulation and short-chain fatty acid (SCFA) production affecting muscle metabolism and preservation, and muscle activity/exercise in turn inducing significant changes in GM composition, functionality, diversity, and SCFA production. This gut–muscle and muscle–gut interplay can then modulate cognition. For instance, irisin, an exercise-induced myokine, promotes neuroplasticity and cognitive function through BDNF signaling. Irisin and muscle-generated BDNF may mediate the positive effects of physical activity against some aspects of AD pathophysiology through the interaction of exercise with the gut microbial ecosystem, neural plasticity, anti-inflammatory signaling pathways, and neurogenesis. Understanding gut–muscle–brain interconnections hold promise for developing strategies to promote brain health, fight age-associated cognitive decline, and improve muscle health and longevity. Full article

(This article belongs to the Special Issue Advances in Neurodegenerative Diseases Research and Therapy 2.0)

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