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New Advances in the Molecular Mechanism and Target Therapy in...
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New Advances in the Molecular Mechanism and Target Therapy in Alzheimer’s Diseases

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (15 December 2022) | Viewed by 17023

Special Issue Editor

Prof. Dr. Rong Liu

E-Mail Website
Guest Editor
Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
Interests: Alzheimer’s disease; phosphorylation; protein phosphatase; hippocampus; brain; spatial memory; learning and memory

Special Issue Information

Dear Colleagues,

Alzheimer’s disease (AD) is the most common type of dementia in the world. The mechanisms of AD pathogenesis are not fully understood, which limit the development of effective clinical interventional strategies. In recent years, with substantial progress in transcriptomes, proteomes, metabolomes, and bioinformatics, new risk factors, key disease-related molecules, and disease mechanisms are constantly being discovered. Emerging findings not only revealed the key disease-related events in neurons, but also implied the important role of glial cells, such as astrocytes and microglia in AD development. Furthermore, lots of peripheral factors, such as systemic inflammation, liver/kidney detoxification/excretion dysfunction, gut microbiota disturbance, and so on, are also found to participate to AD pathogenesis.

In this Special Issue, we focus on the new advances in the molecular mechanism and target therapy in AD. Original papers reporting interesting molecular mechanisms of AD and new molecular targets in AD therapy, as well as review articles summarizing and discussing the advances in the molecular mechanism and target in AD, are welcomed. We hope that this Special Issue is a great success and can promote the understanding of AD pathogenesis and intervention.

Prof. Dr. Rong Liu
Guest Editor

Manuscript Submission Information

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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. Biomolecules 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 2700 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

  • Alzheimer’s disease
  • molecular mechanism
  • target therapy

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Published Papers (5 papers)

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Research

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15 pages, 4316 KiB  
Article
Time- and Sex-Dependent Effects of Fingolimod Treatment in a Mouse Model of Alzheimer’s Disease
by Pablo Bascuñana, Mirjam Brackhan, Luisa Möhle, Jingyun Wu, Thomas Brüning, Ivan Eiriz, Baiba Jansone and Jens Pahnke
Biomolecules 2023, 13(2), 331; https://doi.org/10.3390/biom13020331 - 9 Feb 2023
Cited by 7 | Viewed by 2714
Abstract
Alzheimer’s disease (AD) is the most common cause of dementia. Fingolimod has previously shown beneficial effects in different animal models of AD. However, it has shown contradictory effects when it has been applied at early disease stages. Our objective was to evaluate fingolimod [...] Read more.
Alzheimer’s disease (AD) is the most common cause of dementia. Fingolimod has previously shown beneficial effects in different animal models of AD. However, it has shown contradictory effects when it has been applied at early disease stages. Our objective was to evaluate fingolimod in two different treatment paradigms. To address this aim, we treated male and female APP-transgenic mice for 50 days, starting either before plaque deposition at 50 days of age (early) or at 125 days of age (late). To evaluate the effects, we investigated the neuroinflammatory and glial markers, the Aβ load, and the concentration of the brain-derived neurotrophic factor (BDNF). We found a reduced Aβ load only in male animals in the late treatment paradigm. These animals also showed reduced microglia activation and reduced IL-1β. No other treatment group showed any difference in comparison to the controls. On the other hand, we detected a linear correlation between BDNF and the brain Aβ concentrations. The fingolimod treatment has shown beneficial effects in AD models, but the outcome depends on the neuroinflammatory state at the start of the treatment. Thus, according to our data, a fingolimod treatment would be effective after the onset of the first AD symptoms, mainly affecting the neuroinflammatory reaction to the ongoing Aβ deposition. Full article
(This article belongs to the Special Issue New Advances in the Molecular Mechanism and Target Therapy in Alzheimer’s Diseases)
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13 pages, 2841 KiB  
Article
Licochalcone E, a β-Amyloid Aggregation Inhibitor, Regulates Microglial M1/M2 Polarization via Inhibition of CTL1-Mediated Choline Uptake
by Eisuke Muto, Toshio Okada, Tsuyoshi Yamanaka, Hiroyuki Uchino and Masato Inazu
Biomolecules 2023, 13(2), 191; https://doi.org/10.3390/biom13020191 - 17 Jan 2023
Cited by 5 | Viewed by 2486
Abstract
Alzheimer’s disease (AD) is thought to be a series of neuroinflammatory diseases caused by abnormal deposits of amyloid-β (Aβ) and tau protein in the brain as part of its etiology. We focused on Aβ aggregation and M1 and M2 microglial polarity in microglia [...] Read more.
Alzheimer’s disease (AD) is thought to be a series of neuroinflammatory diseases caused by abnormal deposits of amyloid-β (Aβ) and tau protein in the brain as part of its etiology. We focused on Aβ aggregation and M1 and M2 microglial polarity in microglia to search for novel therapeutic agents. It has been reported that the inhibition of choline uptake via choline transporter-like protein 1 (CTL1) in microglia preferentially induces M2 microglial polarity. However, the role of the choline transport system on the regulation of microglial M1/M2 polarity in AD is not fully understood. Licochalcones (Licos) A–E, flavonoids extracted from licorice, have been reported to have immunological anti-inflammatory effects, and Lico A inhibits Aβ aggregation. In this study, we compared the efficacy of five Licos, from Lico A to E, at inhibiting Aβ1-42 aggregation. Among the five Licos, Lico E was selected to investigate the relationship between the inhibition of choline uptake and microglial M1/M2 polarization using the immortalized mouse microglial cell line SIM-A9. We newly found that Lico E inhibited choline uptake and Aβ1-42 aggregation in SIM-A9 cells in a concentration-dependent manner, suggesting that the inhibitory effect of Lico E on choline uptake is mediated by CTL1. The mRNA expression of tumor necrosis factor (TNF-α), a marker of M1 microglia, was increased by Aβ1-42, and its effect was inhibited by choline deprivation and Lico E in a concentration-dependent manner. In contrast, the mRNA expression of arginase-1 (Arg-1), a marker of M2 microglia, was increased by IL-4, and its effect was enhanced by choline deprivation and Lico E. We found that Lico E has an inhibitory effect on Aβ aggregation and promotes polarity from M1 to M2 microglia via inhibition of the CTL1 function in microglia. Thus, Lico E may become a leading compound for a novel treatment of AD. Full article
(This article belongs to the Special Issue New Advances in the Molecular Mechanism and Target Therapy in Alzheimer’s Diseases)
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14 pages, 3511 KiB  
Article
Insights into Non-Proteolytic Inhibitory Mechanisms of Polymorphic Early-Stage Amyloid β Oligomers by Insulin Degrading Enzyme
by Karina Abramov-Harpaz and Yifat Miller
Biomolecules 2022, 12(12), 1886; https://doi.org/10.3390/biom12121886 - 16 Dec 2022
Cited by 4 | Viewed by 1784
Abstract
Insulin degrading enzyme (IDE) has been detected in the cerebrospinal fluid media and plays a role in encapsulating and degrading the amyloid β (Aβ) monomer, thus regulating the levels of Aβ monomers. The current work illustrates a first study by which IDE encapsulates [...] Read more.
Insulin degrading enzyme (IDE) has been detected in the cerebrospinal fluid media and plays a role in encapsulating and degrading the amyloid β (Aβ) monomer, thus regulating the levels of Aβ monomers. The current work illustrates a first study by which IDE encapsulates polymorphic early-stage Aβ oligomers. The main goal of this study was to investigate the molecular mechanisms of IDE activity on the encapsulated early-stage Aβ dimers: fibril-like and random coil/α-helix dimers. Our work led to several findings. First, when the fibril-like Aβ dimer interacts with IDE-C domain, IDE does not impede the contact between the monomers, but plays a role as a ‘dead-end’ chaperone protein. Second, when the fibril-like Aβ dimer interacts with the IDE-N domain, IDE successfully impedes the contacts between monomers. Third, the inhibitory activity of IDE on random coil/α-helix dimers depends on the stability of the dimer. IDE could impede the contacts between monomers in relatively unstable random coil/α-helix dimers, but gets hard to impede in stable dimers. However, IDE encapsulates stable dimers and could serve as a ‘dead-end’ chaperone. Our results examine the molecular interactions between IDE and the dimers, and between the monomers within the dimers. Hence, this study provides insights into the inhibition mechanisms of the primary nucleation of Aβ aggregation and the basic knowledge for rational design to inhibit Aβ aggregation. Full article
(This article belongs to the Special Issue New Advances in the Molecular Mechanism and Target Therapy in Alzheimer’s Diseases)
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9 pages, 946 KiB  
Article
Head-to-Head Comparison of Different Blood Collecting Tubes for Quantification of Alzheimer’s Disease Biomarkers in Plasma
by Lijun Jiang, Xulong Ding, Wenxiao Wang, Xiaobin Yang, Tao Li and Peng Lei
Biomolecules 2022, 12(9), 1194; https://doi.org/10.3390/biom12091194 - 28 Aug 2022
Cited by 7 | Viewed by 2327
Abstract
To examine whether the type of blood collection tubes affects the quantification of plasma biomarkers for Alzheimer’s disease analyzed with a single-molecule array (Simoa), we recruited a healthy cohort (n = 34, 11 males, mean age = 28.7 ± 7.55) and collected plasma [...] Read more.
To examine whether the type of blood collection tubes affects the quantification of plasma biomarkers for Alzheimer’s disease analyzed with a single-molecule array (Simoa), we recruited a healthy cohort (n = 34, 11 males, mean age = 28.7 ± 7.55) and collected plasma in the following tubes: dipotassium ethylenediaminetetraacetic acid (K2-EDTA), heparin lithium (Li-Hep), and heparin sodium (Na-Hep). Plasma tau, phosphorylated tau 181 (p-tau181), amyloid β (1–40) (Aβ40), and amyloid β (1–42) (Aβ42) were quantified using Simoa. We compared the value of plasma analytes, as well as the effects of sex on the measurements. We found that plasma collected in Li-Hep and Na-Hep tubes yielded significantly higher tau and p-tau181 levels compared to plasma collected in K2-EDTA tubes from the same person, but there was no difference in the measured values of the Aβ40, Aβ42, and Aβ42/40 ratio. Therefore, the type of blood collecting tubes should be considered when planning studies that measure plasma tau. Full article
(This article belongs to the Special Issue New Advances in the Molecular Mechanism and Target Therapy in Alzheimer’s Diseases)
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Review

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20 pages, 2028 KiB  
Review
The Amyloid-Beta Clearance: From Molecular Targets to Glial and Neural Cells
by Wenjun Cai, Tong Wu and Ning Chen
Biomolecules 2023, 13(2), 313; https://doi.org/10.3390/biom13020313 - 7 Feb 2023
Cited by 20 | Viewed by 6997
Abstract
The deposition of amyloid-beta (Aβ) plaques in the brain is one of the primary pathological characteristics of Alzheimer’s disease (AD). It can take place 20–30 years before the onset of clinical symptoms. The imbalance between the production and the clearance of Aβ is [...] Read more.
The deposition of amyloid-beta (Aβ) plaques in the brain is one of the primary pathological characteristics of Alzheimer’s disease (AD). It can take place 20–30 years before the onset of clinical symptoms. The imbalance between the production and the clearance of Aβ is one of the major causes of AD. Enhancing Aβ clearance at an early stage is an attractive preventive and therapeutic strategy of AD. Direct inhibition of Aβ production and aggregation using small molecules, peptides, and monoclonal antibody drugs has not yielded satisfactory efficacy in clinical trials for decades. Novel approaches are required to understand and combat Aβ deposition. Neurological dysfunction is a complex process that integrates the functions of different types of cells in the brain. The role of non-neurons in AD has not been fully elucidated. An in-depth understanding of the interactions between neurons and non-neurons can contribute to the elucidation of Aβ formation and the identification of effective drug targets. AD patient-derived pluripotent stem cells (PSCs) contain complete disease background information and have the potential to differentiate into various types of neurons and non-neurons in vitro, which may bring new insight into the treatment of AD. Here, we systematically review the latest studies on Aβ clearance and clarify the roles of cell interactions among microglia, astroglia and neurons in response to Aβ plaques, which will be beneficial to explore methods for reconstructing AD disease models using inducible PSCs (iPSCs) through cell differentiation techniques and validating the applications of models in understanding the formation of Aβ plaques. This review may provide the most promising directions of finding the clues for preventing and delaying the development of AD. Full article
(This article belongs to the Special Issue New Advances in the Molecular Mechanism and Target Therapy in Alzheimer’s Diseases)
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