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Molecular Mechanisms of Aging-Related Neurodegenerative Diseases
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Molecular Mechanisms of Aging-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 June 2022) | Viewed by 15401

Special Issue Editor

Prof. Dr. Urszula Wojda

E-Mail Website
Guest Editor
Laboratory of Preclinical Testing of Higher Standard, Neurobiology Center, Nencki Institute of Experimental Biology, 3 Pasteur Str., 02-093 Warsaw, Poland
Interests: Alzheimer’s disease; molecular mechanisms of neurodegeneration; diagnostics; prognostics; biomarkers; machine learning; artificial intelligence
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleague,

Aging is the main risk factor for many neurodegenerative diseases, including the most common: Alzheimer’s disease and Parkinson’s disease. These diseases are sporadic in the majority of cases, irreversibly escalate with time, and eventually lead to massive neuronal loss. They represent a large, global socioeconomic burden, with no effective therapies available.

Brain cells are especially sensitive to the aging process, but the pathomechanisms switching non-pathological aging to neurodegenerative disorders are complex and not yet fully elucidated. It seems that neurodegeneration develops gradually as a crosstalk between systemic metabolic and inflammatory changes and the brain and involves impairment in the blood–brain barrier and neuroinflammation. Many genetic, epigenetic, and environmental factors, including infectious agents, can contribute to neurodegeneration. Molecular mechanisms of the pathogenesis comprise, but are not limited to, loss of proteostasis, mitochondrial impairment, oxidative stress, cell cycle dysregulation, genomic instability, and calcium dyshomeostasis. 

As the elucidation of molecular mechanisms and the sequence of pathological events driving neurodegenerative diseases is crucial for the development of efficient therapies, this Special Issue invites submissions of original research articles and short or comprehensive reviews presenting the current developments in this area. Articles with a therapeutic perspective are especially welcome.

Prof. Dr. Urszula Wojda
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Aging
  • Neurodegenerative diseases
  • Alzheimer’s disease
  • Parkinson’s disease
  • Neuroinflammation
  • Oxidative stress
  • Mitochondrial disorder
  • Calcium dyshomeostasis
  • Genomic instability
  • Epigenetic dysregulation
  • Novel therapeutic target

Published Papers (5 papers)

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Research

9 pages, 2323 KiB  
Article
In Vivo Dynamic Movement of Polymerized Amyloid β in the Perivascular Space of the Cerebral Cortex in Mice
by Itsuki Hasegawa, Yoko Hirayoshi, Shinobu Minatani, Toshikazu Mino, Akitoshi Takeda and Yoshiaki Itoh
Int. J. Mol. Sci. 2022, 23(12), 6422; https://doi.org/10.3390/ijms23126422 - 8 Jun 2022
Cited by 1 | Viewed by 1475
Abstract
Disposition of amyloid β (Aβ) into the perivascular space of the cerebral cortex has been recently suggested as a major source of its clearance, and its disturbance may be involved in the pathogenesis of cerebral amyloid angiopathy and Alzheimer’s disease. Here, we explored [...] Read more.
Disposition of amyloid β (Aβ) into the perivascular space of the cerebral cortex has been recently suggested as a major source of its clearance, and its disturbance may be involved in the pathogenesis of cerebral amyloid angiopathy and Alzheimer’s disease. Here, we explored the in vivo dynamics of Aβ in the perivascular space of anesthetized mice. Live images were obtained with two-photon microscopy through a closed cranial window. Either fluorescent-dye-labeled Aβ oligomers prepared freshly or Aβ fibrils after 6 days of incubation at 37 °C were placed over the cerebral cortex. Accumulation of Aβ was observed in the localized perivascular space of the penetrating arteries and veins. Transportation of the accumulated Aβ along the vessels was slow and associated with changes in shape. Aβ oligomers were transported smoothly and separately, whereas Aβ fibrils formed a mass and moved slowly. Parenchymal accumulation of Aβ oligomers, as well as Aβ fibrils along capillaries, increased gradually. In conclusion, we confirmed Aβ transportation between the cortical surface and the deeper parenchyma through the perivascular space that may be affected by the peptide polymerization. Facilitation of Aβ excretion through the system can be a key target in treating Alzheimer’s disease. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Aging-Related Neurodegenerative Diseases)
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36 pages, 9555 KiB  
Article
Induction of Brain Insulin Resistance and Alzheimer’s Molecular Changes by Western Diet
by Anna Mietelska-Porowska, Justyna Domańska, Andrew Want, Angelika Więckowska-Gacek, Dominik Chutorański, Maciej Koperski and Urszula Wojda
Int. J. Mol. Sci. 2022, 23(9), 4744; https://doi.org/10.3390/ijms23094744 - 25 Apr 2022
Cited by 10 | Viewed by 2560
Abstract
The term Western diet (WD) describes the consumption of large amounts of highly processed foods, rich in simple sugars and saturated fats. Long-term WD feeding leads to insulin resistance, postulated as a risk factor for Alzheimer’s disease (AD). AD is the main cause [...] Read more.
The term Western diet (WD) describes the consumption of large amounts of highly processed foods, rich in simple sugars and saturated fats. Long-term WD feeding leads to insulin resistance, postulated as a risk factor for Alzheimer’s disease (AD). AD is the main cause of progressive dementia characterized by the deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles consisting of the hyperphosphorylated tau (p-Tau) protein in the brain, starting from the entorhinal cortex and the hippocampus. In this study, we report that WD-derived impairment in insulin signaling induces tau and Aβ brain pathology in wild-type C57BL/6 mice, and that the entorhinal cortex is more sensitive than the hippocampus to the impairment of brain insulin signaling. In the brain areas developing WD-induced insulin resistance, we observed changes in p-Tau(Thr231) localization in neuronal subcellular compartments, indicating progressive tauopathy, and a decrease in amyloid precursor protein levels correlating with the appearance of Aβ peptides. These results suggest that WD promotes the development of AD and may be considered not only a risk factor, but also a modifiable trigger of AD. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Aging-Related Neurodegenerative Diseases)
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23 pages, 12524 KiB  
Article
Neurodegeneration and Astrogliosis in the Human CA1 Hippocampal Subfield Are Related to hsp90ab1 and bag3 in Alzheimer’s Disease
by Melania Gonzalez-Rodriguez, Sandra Villar-Conde, Veronica Astillero-Lopez, Patricia Villanueva-Anguita, Isabel Ubeda-Banon, Alicia Flores-Cuadrado, Alino Martinez-Marcos and Daniel Saiz-Sanchez
Int. J. Mol. Sci. 2022, 23(1), 165; https://doi.org/10.3390/ijms23010165 - 23 Dec 2021
Cited by 19 | Viewed by 4815
Abstract
Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder, is characterized by executive dysfunction and memory impairment mediated by the accumulation of extracellular amyloid-β peptide (Aβ) and intracellular hyperphosphorylated tau protein. The hippocampus (HIPP) is essential for memory formation and is involved in early [...] Read more.
Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder, is characterized by executive dysfunction and memory impairment mediated by the accumulation of extracellular amyloid-β peptide (Aβ) and intracellular hyperphosphorylated tau protein. The hippocampus (HIPP) is essential for memory formation and is involved in early stages of disease. In fact, hippocampal atrophy is used as an early biomarker of neuronal injury and to evaluate disease progression. It is not yet well-understood whether changes in hippocampal volume are due to neuronal or glial loss. The aim of the study was to assess hippocampal atrophy and/or gliosis using unbiased stereological quantification and to obtain hippocampal proteomic profiles related to neurodegeneration and gliosis. Hippocampal volume measurement, stereological quantification of NeuN-, Iba-1- and GFAP-positive cells, and sequential window acquisition of all theoretical mass spectrometry (SWATH-MS) analysis were performed in AD and non-AD cases. Reduced hippocampal volume was identified using the Cavalieri probe, particularly in the CA1 region, where it correlated with neuronal loss and astrogliosis. A total of 102 downregulated and 47 upregulated proteins were identified in the SWATH-MS analysis after restrictive filtering based on an FC > 1.5 and p value < 0.01. The Hsp90 family of chaperones, particularly BAG3 and HSP90AB1, are closely related to astrocytes, indicating a possible role in degrading Aβ and tau through chaperone-mediated autophagy. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Aging-Related Neurodegenerative Diseases)
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12 pages, 5528 KiB  
Article
(De)stabilization of Alpha-Synuclein Fibrillary Aggregation by Charged and Uncharged Surfactants
by Joana Angélica Loureiro, Stéphanie Andrade, Lies Goderis, Ruben Gomez-Gutierrez, Claudio Soto, Rodrigo Morales and Maria Carmo Pereira
Int. J. Mol. Sci. 2021, 22(22), 12509; https://doi.org/10.3390/ijms222212509 - 19 Nov 2021
Cited by 3 | Viewed by 2226
Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative disorder. An important hallmark of PD involves the pathological aggregation of proteins in structures known as Lewy bodies. The major component of these proteinaceous inclusions is alpha (α)-synuclein. In different conditions, α-synuclein can assume [...] Read more.
Parkinson’s disease (PD) is the second most common neurodegenerative disorder. An important hallmark of PD involves the pathological aggregation of proteins in structures known as Lewy bodies. The major component of these proteinaceous inclusions is alpha (α)-synuclein. In different conditions, α-synuclein can assume conformations rich in either α-helix or β-sheets. The mechanisms of α-synuclein misfolding, aggregation, and fibrillation remain unknown, but it is thought that β-sheet conformation of α-synuclein is responsible for its associated toxic mechanisms. To gain fundamental insights into the process of α-synuclein misfolding and aggregation, the secondary structure of this protein in the presence of charged and non-charged surfactant solutions was characterized. The selected surfactants were (anionic) sodium dodecyl sulphate (SDS), (cationic) cetyltrimethylammonium chloride (CTAC), and (uncharged) octyl β-D-glucopyranoside (OG). The effect of surfactants in α-synuclein misfolding was assessed by ultra-structural analyses, in vitro aggregation assays, and secondary structure analyses. The α-synuclein aggregation in the presence of negatively charged SDS suggests that SDS-monomer complexes stimulate the aggregation process. A reduction in the electrostatic repulsion between N- and C-terminal and in the hydrophobic interactions between the NAC (non-amyloid beta component) region and the C-terminal seems to be important to undergo aggregation. Fourier transform infrared spectroscopy (FTIR) measurements show that β-sheet structures comprise the assembly of the fibrils. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Aging-Related Neurodegenerative Diseases)
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16 pages, 3421 KiB  
Article
The ALS-Associated FUS (P525L) Variant Does Not Directly Interfere with Microtubule-Dependent Kinesin-1 Motility
by Anne Seifert, Hauke Drechsler, Julia Japtok, Till Korten, Stefan Diez and Andreas Hermann
Int. J. Mol. Sci. 2021, 22(5), 2422; https://doi.org/10.3390/ijms22052422 - 28 Feb 2021
Cited by 1 | Viewed by 3179
Abstract
Deficient intracellular transport is a common pathological hallmark of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Mutations in the fused-in-sarcoma (FUS) gene are one of the most common genetic causes for familial ALS. Motor neurons carrying a mutation in the nuclear localization [...] Read more.
Deficient intracellular transport is a common pathological hallmark of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Mutations in the fused-in-sarcoma (FUS) gene are one of the most common genetic causes for familial ALS. Motor neurons carrying a mutation in the nuclear localization sequence of FUS (P525L) show impaired axonal transport of several organelles, suggesting that mislocalized cytoplasmic FUS might directly interfere with the transport machinery. To test this hypothesis, we studied the effect of FUS on kinesin-1 motility in vitro. Using a modified microtubule gliding motility assay on surfaces coated with kinesin-1 motor proteins, we showed that neither recombinant wildtype and P525L FUS variants nor lysates from isogenic ALS-patient-specific iPSC-derived spinal motor neurons expressing those FUS variants significantly affected gliding velocities. We hence conclude that during ALS pathogenesis the initial negative effect of FUS (P525L) on axonal transport is an indirect nature and requires additional factors or mechanisms. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Aging-Related Neurodegenerative Diseases)
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