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Molecular Mechanism in the Pathogenesis of Alzheimer’s Disease and Related Neurodegenerative Diseases

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 October 2024) | Viewed by 8650

Special Issue Editor

Dr. Kun Zou

E-Mail Website
Guest Editor
Department of Biochemistry, Nagoya City University Graduate School of Medical Sciences, Kawasumi 1, Nagoya 467-8601, Japan
Interests: Alzheimer’s disease; amyloid protein; amyloid degradation; alpha-synuclein; TDP-43; blood–brain barrier; presenilin; neurodegenerative diseases

Special Issue Information

Dear Colleagues,

Alzheimer’s disease (AD) and related neurodegenerative disorders are complex conditions with intricate molecular underpinnings. AD often shares pathological features with other neurodegenerative diseases, including Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Common mechanisms include protein misfolding, aggregation, and accumulation, leading to the formation of characteristic pathological structures, such as amyloid plaques and neurofibrillary tangles. In AD, pathogenesis involves multiple interconnected mechanisms. The aggregation of amyloid-β (Aβ) peptides and the formation of neurofibrillary tangles due to hyperphosphorylated tau proteins lead to synaptic dysfunction and neuronal loss. Additionally, the dysregulation of calcium homeostasis, oxidative stress, and mitochondrial dysfunction contribute to pathogenesis. Emerging evidence suggests the involvement of inflammation, where microglial activation and astrocytic response perpetuate neuronal damage.

Moreover, dysfunctions in proteostasis, including impaired autophagy and ubiquitin-proteasome system activity, contribute to the accumulation of misfolded proteins, exacerbating neurodegeneration. Aberrant lipid metabolism and disrupted signaling cascades, such as the Wnt and insulin signaling pathways, further contribute to disease progression. Furthermore, genetic predisposition, including the role of apolipoprotein E (APOE) alleles, plays a crucial role in disease susceptibility.

Understanding these intricate molecular mechanisms holds promise for the development of targeted therapeutic interventions, such as Aβ aggregation inhibitors, tau-directed therapies, anti-inflammatory agents, and modulators of proteostasis. Integrative research efforts are needed to unravel the complex interplay between these mechanisms and to develop effective strategies for the prevention and treatment of Alzheimer's Disease and related neurodegenerative disorders.

Dr. Kun Zou
Guest Editor

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Keywords

  • Alzheimer’s disease
  • neurodegenerative diseases
  • Parkinson’s disease
  • amyotrophic lateral sclerosis
  • molecular mechanism
  • neuronal death
  • amyloid beta-protein
  • Tau
  • alpha-synuclein
  • TDP43
 

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Published Papers (5 papers)

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Research

13 pages, 2450 KiB  
Article
Comparison of Methods of Detecting IL-1β in the Blood of Alzheimer’s Disease Subjects
by Alexandra D. Remnitz, Roey Hadad, Robert W. Keane, W. Dalton Dietrich and Juan Pablo de Rivero Vaccari
Int. J. Mol. Sci. 2025, 26(2), 831; https://doi.org/10.3390/ijms26020831 - 20 Jan 2025
Cited by 1 | Viewed by 1339
Abstract
Interleukin (IL)-1β is a pro-inflammatory cytokine whose levels are increased in the brains of Alzheimer’s disease (AD) patients. Despite the role of IL-1β in the pathology of AD, the fact that it is expressed at very low levels makes it a challenging cytokine [...] Read more.
Interleukin (IL)-1β is a pro-inflammatory cytokine whose levels are increased in the brains of Alzheimer’s disease (AD) patients. Despite the role of IL-1β in the pathology of AD, the fact that it is expressed at very low levels makes it a challenging cytokine to measure, hence limiting its potential use as a reliable biomarker. Moreover, being able to accurately and reliably measure the levels of IL-1 β in blood makes it possible to evaluate this cytokine as a potential biomarker of the inflammatory response in AD. In this study, we compared three quantification methodologies, Meso-Scale Discovery (MSD), both V-Plex and S-Plex versions, and Quanterix’s SIMOA (Single-Molecule Array), to measure IL-1β in the serum of AD patients and age-matched controls. These assays are routinely used to measure IL-1β serum levels with high specificity and sensitivity in human AD patients, yet to the best of our knowledge, no study has compared all three techniques for their accuracy to measure IL-1β as biomarkers. Our findings indicate the two MSD assays can be used to measure IL-1β levels in AD and control serum, but the SIMOA assay showed the highest receiver operating characteristics (ROCs), with an area under the curve (AUC) of 0.9532, which can be compared to the AUC values for the V-Plex assay, 0.5660, and the S-Plex assay, 0.6632. Taken together, these data show that although all technologies are useful in the measurement of IL-1β in the blood, the SIMOA IL-1β 3.0 assay is more reliable and sensitive in measuring biomarkers of AD. Full article
(This article belongs to the Special Issue Molecular Mechanism in the Pathogenesis of Alzheimer’s Disease and Related Neurodegenerative Diseases)
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15 pages, 5051 KiB  
Article
Chronological Dynamics of Neuroinflammatory Responses in a High-Fat Diet Mouse Model
by Heekyong R. Bae, Su-Kyung Shin, Ji-Yoon Lee, Seong-Su Choi and Eun-Young Kwon
Int. J. Mol. Sci. 2024, 25(23), 12834; https://doi.org/10.3390/ijms252312834 - 29 Nov 2024
Viewed by 1176
Abstract
Obesity is known to affect various tissues and contribute to conditions such as neuroinflammation. However, the specific mechanisms and time-dependent progression of these effects across different tissues remain unclear. In this study, we monitored gene expression at intervals to examine the effects of [...] Read more.
Obesity is known to affect various tissues and contribute to conditions such as neuroinflammation. However, the specific mechanisms and time-dependent progression of these effects across different tissues remain unclear. In this study, we monitored gene expression at intervals to examine the effects of a high-fat diet (HFD) on brain, liver, adipose, and muscle tissues in male C57/BJ mice, with a particular focus on neuroinflammation. Early inflammatory responses exhibit a progression that starts in the liver, extends to adipose tissue, and subsequently involves muscle and brain tissues. Although the brain did not show significant gene expression of inflammatory responses, mechanisms leading to neuroinflammation increased after 24 weeks, possibly through systemic chronic inflammation (SCI). Notably, mitochondrial complex I activity serves as a biomarker to indicate the inflammatory transition from the liver to adipose and other tissues caused by SCI. These similar gene expression dynamics were also observed in the hippocampus of Alzheimer’s patients and in an Alzheimer’s mouse model treated with a HFD. These results suggest that initially, the brain suppresses inflammatory responses, including interferon-gamma (IFN-γ), more than other tissues in response to a HFD. However, at the onset of SCI, the brain eventually exhibits inflammatory dynamics similar to those of other tissues. This underscores the significance of our findings, indicating that the early kinetics of chronic IFN-γ response and mitochondrial complex I activity inhibition serve as crucial biomarkers, emerging early in various conditions, including obesity and aging. Full article
(This article belongs to the Special Issue Molecular Mechanism in the Pathogenesis of Alzheimer’s Disease and Related Neurodegenerative Diseases)
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12 pages, 1204 KiB  
Communication
Serum Beta-Secretase 1 Activity Is a Potential Marker for the Differential Diagnosis between Alzheimer’s Disease and Frontotemporal Dementia: A Pilot Study
by Claudia Saraceno, Carlo Cervellati, Alessandro Trentini, Daniela Crescenti, Antonio Longobardi, Andrea Geviti, Natale Salvatore Bonfiglio, Sonia Bellini, Roland Nicsanu, Silvia Fostinelli, Gianmarco Mola, Raffaella Riccetti, Davide Vito Moretti, Orazio Zanetti, Giuliano Binetti, Giovanni Zuliani and Roberta Ghidoni
Int. J. Mol. Sci. 2024, 25(15), 8354; https://doi.org/10.3390/ijms25158354 - 30 Jul 2024
Cited by 4 | Viewed by 1626
Abstract
Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are the two major neurodegenerative diseases causing dementia. Due to similar clinical phenotypes, differential diagnosis is challenging without specific biomarkers. Beta-site Amyloid Precursor Protein cleaving enzyme 1 (BACE1) is a β-secretase pivotal in AD pathogenesis. In [...] Read more.
Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are the two major neurodegenerative diseases causing dementia. Due to similar clinical phenotypes, differential diagnosis is challenging without specific biomarkers. Beta-site Amyloid Precursor Protein cleaving enzyme 1 (BACE1) is a β-secretase pivotal in AD pathogenesis. In AD and mild cognitive impairment subjects, BACE1 activity is increased in brain/cerebrospinal fluid, and plasma levels appear to reflect those in the brain. In this study, we aim to evaluate serum BACE1 activity in FTD, since, to date, there is no evidence about its role. The serum of 30 FTD patients and 30 controls was analyzed to evaluate (i) BACE1 activity, using a fluorescent assay, and (ii) Glial Fibrillary Acid Protein (GFAP) and Neurofilament Light chain (NfL) levels, using a Simoa kit. As expected, a significant increase in GFAP and NfL levels was observed in FTD patients compared to controls. Serum BACE1 activity was not altered in FTD patients. A significant increase in serum BACE1 activity was shown in AD vs. FTD and controls. Our results support the hypothesis that serum BACE1 activity is a potential biomarker for the differential diagnosis between AD and FTD. Full article
(This article belongs to the Special Issue Molecular Mechanism in the Pathogenesis of Alzheimer’s Disease and Related Neurodegenerative Diseases)
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13 pages, 1400 KiB  
Article
Methionine Sulfoxide Speciation in Mouse Hippocampus Revealed by Global Proteomics Exhibits Age- and Alzheimer’s Disease-Dependent Changes Targeted to Mitochondrial and Glycolytic Pathways
by Filipa Blasco Tavares Pereira Lopes, Daniela Schlatzer, Mengzhen Li, Serhan Yilmaz, Rihua Wang, Xin Qi, Marzieh Ayati, Mehmet Koyutürk and Mark R. Chance
Int. J. Mol. Sci. 2024, 25(12), 6516; https://doi.org/10.3390/ijms25126516 - 13 Jun 2024
Cited by 1 | Viewed by 1721
Abstract
Methionine oxidation to the sulfoxide form (MSox) is a poorly understood post-translational modification of proteins associated with non-specific chemical oxidation from reactive oxygen species (ROS), whose chemistries are linked to various disease pathologies, including neurodegeneration. Emerging evidence shows MSox site [...] Read more.
Methionine oxidation to the sulfoxide form (MSox) is a poorly understood post-translational modification of proteins associated with non-specific chemical oxidation from reactive oxygen species (ROS), whose chemistries are linked to various disease pathologies, including neurodegeneration. Emerging evidence shows MSox site occupancy is, in some cases, under enzymatic regulatory control, mediating cellular signaling, including phosphorylation and/or calcium signaling, and raising questions as to the speciation and functional nature of MSox across the proteome. The 5XFAD lineage of the C57BL/6 mouse has well-defined Alzheimer’s and aging states. Using this model, we analyzed age-, sex-, and disease-dependent MSox speciation in the mouse hippocampus. In addition, we explored the chemical stability and statistical variance of oxidized peptide signals to understand the needed power for MSox-based proteome studies. Our results identify mitochondrial and glycolytic pathway targets with increases in MSox with age as well as neuroinflammatory targets accumulating MSox with AD in proteome studies of the mouse hippocampus. Further, this paper establishes a foundation for reproducible and rigorous experimental MSox-omics appropriate for novel target identification in biological discovery and for biomarker analysis in ROS and other oxidation-linked diseases. Full article
(This article belongs to the Special Issue Molecular Mechanism in the Pathogenesis of Alzheimer’s Disease and Related Neurodegenerative Diseases)
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19 pages, 3399 KiB  
Article
Genome-Wide DNA Methylation in Early-Onset-Dementia Patients Brain Tissue and Lymphoblastoid Cell Lines
by Oscar Ramos-Campoy, Aina Comas-Albertí, David Hervás, Sergi Borrego-Écija, Beatriz Bosch, Juan Sandoval, Laura Fort-Aznar, Fermín Moreno-Izco, Guadalupe Fernández-Villullas, Laura Molina-Porcel, Mircea Balasa, Albert Lladó, Raquel Sánchez-Valle and Anna Antonell
Int. J. Mol. Sci. 2024, 25(10), 5445; https://doi.org/10.3390/ijms25105445 - 16 May 2024
Viewed by 2026
Abstract
Epigenetics, a potential underlying pathogenic mechanism of neurodegenerative diseases, has been in the scope of several studies performed so far. However, there is a gap in regard to analyzing different forms of early-onset dementia and the use of Lymphoblastoid cell lines (LCLs). We [...] Read more.
Epigenetics, a potential underlying pathogenic mechanism of neurodegenerative diseases, has been in the scope of several studies performed so far. However, there is a gap in regard to analyzing different forms of early-onset dementia and the use of Lymphoblastoid cell lines (LCLs). We performed a genome-wide DNA methylation analysis on sixty-four samples (from the prefrontal cortex and LCLs) including those taken from patients with early-onset forms of Alzheimer’s disease (AD) and frontotemporal dementia (FTD) and healthy controls. A beta regression model and adjusted p-values were used to obtain differentially methylated positions (DMPs) via pairwise comparisons. A correlation analysis of DMP levels with Clariom D array gene expression data from the same cohort was also performed. The results showed hypermethylation as the most frequent finding in both tissues studied in the patient groups. Biological significance analysis revealed common pathways altered in AD and FTD patients, affecting neuron development, metabolism, signal transduction, and immune system pathways. These alterations were also found in LCL samples, suggesting the epigenetic changes might not be limited to the central nervous system. In the brain, CpG methylation presented an inverse correlation with gene expression, while in LCLs, we observed mainly a positive correlation. This study enhances our understanding of the biological pathways that are associated with neurodegeneration, describes differential methylation patterns, and suggests LCLs are a potential cell model for studying neurodegenerative diseases in earlier clinical phases than brain tissue. Full article
(This article belongs to the Special Issue Molecular Mechanism in the Pathogenesis of Alzheimer’s Disease and Related Neurodegenerative Diseases)
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