Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
5.2
3.9
Journals
Biomedicines
Special Issues
New Molecular Insights into the Pathogenesis and Drug Development of...
share announcement

New Molecular Insights into the Pathogenesis and Drug Development of Neurodegenerative Diseases

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: 31 January 2025 | Viewed by 8169

Special Issue Editors

Dr. Aifang Cheng

E-Mail Website
Guest Editor
Faculty of Health Sciences, University of Macau, Taipa, Macau
Interests: neurodegenerative diseases; Alzheimer's disease; amyotrophic lateral sclerosis; ataxia–telangiectasia; pathogenesis; molecular mechanisms; drug screening; pharmacological evaluations; drug repurposing; preclinical study
Dr. Beika Zhu

E-Mail Website
Guest Editor
Department of Pediatrics, University of California, San Francisco, CA, USA
Interests: neurodegenerative diseases; Alzheimer's disease; glial biology; microglial function; neuroinflammation; neuroimmune interactions; G protein-coupled receptor; molecular signaling pathway; therapeutic strategies

Special Issue Information

Dear Colleagues,

The prevalence of neurodegenerative diseases is rapidly increasing with the aging trend of global populations, severely threatening human health and creating a societal burden; existing drugs in the market temporarily relieve symptoms but cannot prevent disease progression. Therefore, the development of more effective drugs for neurodegenerative diseases using efficient strategies has become a pressing need. One of the challenges for drug development is the incomplete understanding of the underlying mechanisms of disease pathogenesis.

This Special Issue aims to collect high-quality papers featuring emerging research areas in neurodegenerative diseases, with a particular emphasis on the cellular and molecular mechanisms of disease pathogenesis. It also highlights novel drug discovery targeting neurodegeneration, drug repurposing, mode of action studies on drug leads, and pharmacological evaluations of different models, such as brain organoids and animals. Overall, we hope that this Special Issue will provide a theoretical and technical basis for further preclinical and clinical studies, as well as promote the translational application of valuable candidates as potential therapeutic agents in treating neurodegenerative diseases.

Dr. Aifang Cheng
Dr. Beika Zhu
Guest Editors

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. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). 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

  • neurodegenerative diseases
  • pathogenesis
  • molecular mechanisms
  • high-throughput drug screening
  • drug repurposing
  • cellular and animal models
  • brain organoids
  • mode of action
  • pharmacological evaluations
  • preclinical study

Benefits of Publishing in a Special Issue

  • Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
  • Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
  • Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
  • External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
  • e-Book format: Special Issues with more than 10 articles can be published as dedicated e-books, ensuring wide and rapid dissemination.

Further information on MDPI's Special Issue polices can be found here.

Published Papers (5 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Research

Jump to: Other

18 pages, 5405 KiB  
Article
Altered PLCβ/IP3/Ca2+ Signaling Pathway Activated by GPRCs in Olfactory Neuronal Precursor Cells Derived from Patients Diagnosed with Schizophrenia
by Zuly A. Sánchez-Florentino, Bianca S. Romero-Martínez, Edgar Flores-Soto, Luis M. Montaño, Bettina Sommer, Marcela Valdés-Tovar, Jesús Argueta, Eduardo Calixto, Arnoldo Aquino-Gálvez, Manuel Castillejos-López, Héctor Serrano, Juan C. Gomez-Verjan, Germán O. López-Riquelme, Gloria A. Benítez-King, Ruth Jaimez and Héctor Solís-Chagoyán
Biomedicines 2024, 12(10), 2343; https://doi.org/10.3390/biomedicines12102343 - 15 Oct 2024
Viewed by 1372
Abstract
Background: Schizophrenia (SZ) is a multifactorial chronic psychiatric disorder with a worldwide prevalence of 1%. Altered expression of PLCβ occurs in SZ patients, suggesting alterations in the PLCβ/IP3/Ca2+ signaling pathway. This cascade regulates critical cellular processes in all cell [...] Read more.
Background: Schizophrenia (SZ) is a multifactorial chronic psychiatric disorder with a worldwide prevalence of 1%. Altered expression of PLCβ occurs in SZ patients, suggesting alterations in the PLCβ/IP3/Ca2+ signaling pathway. This cascade regulates critical cellular processes in all cell types, including the neuronal lineage; however, there is scarce evidence regarding the functionality of this transduction signaling in neuronal cells derived from SZ patients. Objective: We evaluated the functionality of the PLCβ/IP3/Ca2+ pathway in olfactory neuronal precursor cells (hONPCs) obtained from SZ patients. Methods: Cryopreserved hONPCs isolated from SZ patients and healthy subjects (HS) were thawed. The cellular types in subcultures were corroborated by immunodetection of the multipotency and lineage markers SOX-2, Musashi-1, nestin, and β-III tubulin. The PLCβ/IP3/Ca2+ pathway was activated by GPCR (Gq) ligands (ATP, UTP, serotonin, and epinephrine). In addition, PLCβ and IP3R were directly stimulated by perfusing cells with the activators m-3M3FBS and ADA, respectively. Cytosolic Ca2+ was measured by microfluorometry and by Ca2+ imaging. The amount and subcellular distribution of the PLCβ1 and PLCβ3 isoforms were evaluated by confocal immunofluorescence. IP3 concentration was measured by ELISA. Results: The results show that the increase of cytosolic Ca2+ triggered by GPCR ligands or directly through either PLCβ or IP3R activation was significantly lower in SZ-derived hONPCs, regarding HS-derived cells. Moreover, the relative amount of the PLCβ1 and PLCβ3 isoforms and IP3 production stimulated with m-3M3FBS were reduced in SZ-derived cells. Conclusions: Our results suggest an overall functional impairment in the PLCβ/IP3/Ca2+ signaling pathway in SZ-derived hONPCs. Full article
(This article belongs to the Special Issue New Molecular Insights into the Pathogenesis and Drug Development of Neurodegenerative Diseases)
►▼ Show Figures

Figure 1

26 pages, 3550 KiB  
Article
Preconditioning of Mesenchymal Stem Cells Enhances the Neuroprotective Effects of Their Conditioned Medium in an Alzheimer’s Disease In Vitro Model
by Tatiana Tolstova, Ekaterina Dotsenko, Natalia Luzgina and Alexander Rusanov
Biomedicines 2024, 12(10), 2243; https://doi.org/10.3390/biomedicines12102243 - 2 Oct 2024
Viewed by 1147
Abstract
Background: Alzheimer’s disease (AD) develops as a result of oxidative damage to neurons and chronic inflammation of microglia. These processes can be influenced by the use of a conditioned medium (CM) derived from mesenchymal stem cells (MSCs). The CM contains a wide range [...] Read more.
Background: Alzheimer’s disease (AD) develops as a result of oxidative damage to neurons and chronic inflammation of microglia. These processes can be influenced by the use of a conditioned medium (CM) derived from mesenchymal stem cells (MSCs). The CM contains a wide range of factors that have neurotrophic, antioxidant, and anti-inflammatory effects. In addition, the therapeutic potential of the CM can be further enhanced by pretreating the MSCs to increase their paracrine activity. The current study aimed to investigate the neuroprotective effects of CM derived from MSCs, which were either activated by a TLR3 ligand or exposed to CoCl2, a hypoxia mimetic (pCM or hCM, respectively), in an in vitro model of AD. Methods: We have developed a novel in vitro model of AD that allows us to investigate the neuroprotective and anti-inflammatory effects of MSCs on induced neurodegeneration in the PC12 cell line and the activation of microglia using THP-1 cells. Results: This study demonstrates for the first time that pCM and hCM exhibit more pronounced immunosuppressive effects on proinflammatory M1 macrophages compared to CM derived from untreated MSCs (cCM). This may help prevent the development of neuroinflammation by balancing the M1 and M2 microglial phenotypes via the decreased secretion of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) and increased secretion of IL-4, as well as the expression of IL-10 and TGF-β by macrophages. Moreover, a previously unknown increase in the neurotrophic properties of hCM was discovered, which led to an increase in the viability of neuron-like PC12 cells under H2O2-induced oxidative-stress conditions. These results are likely associated with an increase in the production of growth factors, including vascular endothelial growth factor (VEGF). In addition, the neuroprotective effects of CM from preconditioned MSCs are also mediated by the activation of the Nrf2/ARE pathway in PC12 cells. Conclusions: TLR3 activation in MSCs leads to more potent immunosuppressive effects of the CM against pro-inflammatory M1 macrophages, while the use of hCM led to increased neurotrophic effects after H2O2-induced damage to neuronal cells. These results are of interest for the potential treatment of AD with CM from preactivated MSCs. Full article
(This article belongs to the Special Issue New Molecular Insights into the Pathogenesis and Drug Development of Neurodegenerative Diseases)
►▼ Show Figures

Figure 1

19 pages, 3764 KiB  
Article
Rasagiline Exerts Neuroprotection towards Oxygen–Glucose-Deprivation/Reoxygenation-Induced GAPDH-Mediated Cell Death by Activating Akt/Nrf2 Signaling
by Shimon Lecht, Adi Lahiani, Michal Klazas, Majdi Saleem Naamneh, Limor Rubin, Jiayi Dong, Wenhua Zheng and Philip Lazarovici
Biomedicines 2024, 12(7), 1592; https://doi.org/10.3390/biomedicines12071592 - 17 Jul 2024
Viewed by 1036
Abstract
Rasagiline (Azilect®) is a selective monoamine oxidase B (MAO-B) inhibitor that provides symptomatic benefits in Parkinson’s disease (PD) treatment and has been found to exert preclinical neuroprotective effects. Here, we investigated the neuroprotective signaling pathways of acute rasagiline treatment for 22 [...] Read more.
Rasagiline (Azilect®) is a selective monoamine oxidase B (MAO-B) inhibitor that provides symptomatic benefits in Parkinson’s disease (PD) treatment and has been found to exert preclinical neuroprotective effects. Here, we investigated the neuroprotective signaling pathways of acute rasagiline treatment for 22 h in PC12 neuronal cultures exposed to oxygen–glucose deprivation (OGD) for 4 h, followed by 18 h of reoxygenation (R), causing 40% aponecrotic cell death. In this study, 3–10 µM rasagiline induced dose-dependent neuroprotection of 20–80%, reduced the production of the neurotoxic reactive oxygen species by 15%, and reduced the nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) by 75–90%. In addition, 10 µM rasagiline increased protein kinase B (Akt) phosphorylation by 50% and decreased the protein expression of the ischemia-induced α-synuclein protein by 50% in correlation with the neuroprotective effect. Treatment with 1–5 µM rasagiline induced nuclear shuttling of transcription factor Nrf2 by 40–90% and increased the mRNA levels of the antioxidant enzymes heme oxygenase-1, (NAD (P) H- quinone dehydrogenase, and catalase by 1.8–2.0-fold compared to OGD/R insult. These results indicate that rasagiline provides neuroprotection to the ischemic neuronal cultures through the inhibition of α-synuclein and GAPDH-mediated aponecrotic cell death, as well as via mitochondrial protection, by increasing mitochondria-specific antioxidant enzymes through a mechanism involving the Akt/Nrf2 redox-signaling pathway. These findings may be exploited for neuroprotective drug development in PD and stroke therapy. Full article
(This article belongs to the Special Issue New Molecular Insights into the Pathogenesis and Drug Development of Neurodegenerative Diseases)
►▼ Show Figures

Graphical abstract

17 pages, 3646 KiB  
Article
DNA Damage and Senescence in the Aging and Alzheimer’s Disease Cortex Are Not Uniformly Distributed
by Gnanesh Gutta, Jay Mehta, Rody Kingston, Jiaan Xie, Eliana Brenner, Fulin Ma and Karl Herrup
Biomedicines 2024, 12(6), 1327; https://doi.org/10.3390/biomedicines12061327 - 14 Jun 2024
Viewed by 1407
Abstract
Alzheimer’s disease (AD) is a neurodegenerative illness with a typical age of onset exceeding 65 years of age. The age dependency of the condition led us to track the appearance of DNA damage in the frontal cortex of individuals who died with a [...] Read more.
Alzheimer’s disease (AD) is a neurodegenerative illness with a typical age of onset exceeding 65 years of age. The age dependency of the condition led us to track the appearance of DNA damage in the frontal cortex of individuals who died with a diagnosis of AD. The focus on DNA damage was motivated by evidence that increasing levels of irreparable DNA damage are a major driver of the aging process. The connection between aging and the loss of genomic integrity is compelling because DNA damage has also been identified as a possible cause of cellular senescence. The number of senescent cells has been reported to increase with age, and their senescence-associated secreted products are likely contributing factors to age-related illnesses. We tracked DNA damage with 53BP1 and cellular senescence with p16 immunostaining of human post-mortem brain samples. We found that DNA damage was significantly increased in the BA9 region of the AD cortex compared with the same region in unaffected controls (UCs). In the AD but not UC cases, the density of cells with DNA damage increased with distance from the pia mater up to approximately layer V and then decreased in deeper areas. This pattern of DNA damage was overlaid with the pattern of cellular senescence, which also increased with cortical depth. On a cell-by-cell basis, we found that the intensities of the two markers were tightly linked in the AD but not the UC brain. To test whether DNA damage was a causal factor in the emergence of the senescence program, we used etoposide treatment to damage the DNA of cultured mouse primary neurons. While DNA damage increased after treatment, after 24 h, no change in the expression of senescence-associated markers was observed. Our work suggests that DNA damage and cellular senescence are both increased in the AD brain and increasingly coupled. We propose that in vivo, the relationship between the two age-related processes is more complex than previously thought. Full article
(This article belongs to the Special Issue New Molecular Insights into the Pathogenesis and Drug Development of Neurodegenerative Diseases)
►▼ Show Figures

Figure 1

Other

Jump to: Research

14 pages, 1669 KiB  
Case Report
PSEN2 Mutations May Mimic Frontotemporal Dementia: Two New Case Reports and a Review
by Anxo Manuel Minguillón Pereiro, Beatriz Quintáns Castro, Alberto Ouro Villasante, José Manuel Aldrey Vázquez, Julia Cortés Hernández, Marta Aramburu-Núñez, Manuel Arias Gómez, Isabel Jiménez Martín, Tomás Sobrino and Juan Manuel Pías-Peleteiro
Biomedicines 2024, 12(8), 1881; https://doi.org/10.3390/biomedicines12081881 - 17 Aug 2024
Viewed by 1954
Abstract
Background: Monogenic Alzheimer’s disease (AD) has severe health and socioeconomic repercussions. Its rarest cause is presenilin 2 (PSEN2) gene mutations. We present two new cases with presumed PSEN2-AD with unusual clinical and neuroimaging findings in order to provide more information on [...] Read more.
Background: Monogenic Alzheimer’s disease (AD) has severe health and socioeconomic repercussions. Its rarest cause is presenilin 2 (PSEN2) gene mutations. We present two new cases with presumed PSEN2-AD with unusual clinical and neuroimaging findings in order to provide more information on the pathophysiology and semiology of these patients. Methods: Women aged 69 and 62 years at clinical onset, marked by prominent behavioral and language dysfunction, progressing to severe dementia within three years were included. The complete study is depicted. In addition, a systematic review of the PSEN2-AD was performed. Results: Neuroimaging revealed pronounced frontal white matter hyperintensities (WMH) and frontotemporal atrophy/hypometabolism. The genetic study unveiled PSEN2 variants: c.772G>A (p.Ala258Thr) and c.1073-2_1073-1del. Both cerebrospinal fluid (CSF) and experimental blood biomarkers shouldered AD etiology. Conclusions: Prominent behavioral and language dysfunction suggesting frontotemporal dementia (FTD) may be underestimated in the literature as a clinical picture in PSEN2 mutations. Thus, it may be reasonable to include PSEN2 in genetic panels when suspecting FTDL. PSEN2 mutations may cause striking WMH, arguably related to myelin disruption induced by amyloid accumulation. Full article
(This article belongs to the Special Issue New Molecular Insights into the Pathogenesis and Drug Development of Neurodegenerative Diseases)
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-5
Back to TopTop