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Alzheimer’s Disease: From Molecular Basis to Therapy 2.0
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Alzheimer’s Disease: From Molecular Basis to Therapy 2.0

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 (15 December 2023) | Viewed by 7534

Special Issue Editor

Dr. Greg T. Sutherland

E-Mail Website
Guest Editor
Charles Perkins Centre and School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW 2050, Australia
Interests: neuropathology; brain transcriptomics; neurogenetics; Alzheimer’s disease; alcohol-related brain injury
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Alzheimer’s disease (AD) manifests as a chronic deterioration in cognition, primarily in memory, resulting from neuronal loss in specific regions of the brain. Beta-amyloid build-up is a key process in the disease, but efforts to pharmaceutically reduce beta-amyloid have not resulted in an expected slowing of cognitive decline. In our first edition of this Special Issue, authors shared their ideas for new or adjunctive therapeutic approaches in AD. In this second edition, we take a step back to ask whether our concept of Alzheimer's disease is too narrow and is this stymieing our progress towards cures. Here, the advances in neuroimaging, and the idea of networks rather than regions underpinning brain function seems important, as are the advances being made bridging genotype and phenotype with powerful epidemiological studies, such as the UK Biobank. Similarly, -Omic data, and particularly that generated at the single cell level is exciting, but the current knowledge gap between molecular data and human behaviour is better described as an abyss. Authors are, therefore, invited to submit original research or review articles on new ways of conceiving AD, and/or the tools they have developed to decipher data pertaining to this complex disease towards novel therapeutic avenues or preventive strategies.

Dr. Greg T. Sutherland
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

  • Alzheimer’s disease
  • risk factors
  • multi-omics
  • systems biology
  • machine learning
  • clinical samples
  • model systems
  • drug discovery
  • precision medicine and precision prevention

Published Papers (4 papers)

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Research

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17 pages, 3791 KiB  
Article
Pharmacological Inhibition of the Asparaginyl Endopeptidase (AEP) in an Alzheimer’s Disease Model Improves the Survival and Efficacy of Transplanted Neural Stem Cells
by Qing Cheng, Xiaoli Ma, Jingjing Liu, Xuemei Feng, Yan Liu, Yanxia Wang, Wenwen Ni and Mingke Song
Int. J. Mol. Sci. 2023, 24(9), 7739; https://doi.org/10.3390/ijms24097739 - 23 Apr 2023
Cited by 1 | Viewed by 1592
Abstract
Stem-cell-based therapy is very promising for Alzheimer’s disease (AD), yet has not become a reality. A critical challenge is the transplantation microenvironment, which impacts the therapeutic effect of stem cells. In AD brains, amyloid-beta (Aβ) peptides and inflammatory cytokines continuously poison the tissue [...] Read more.
Stem-cell-based therapy is very promising for Alzheimer’s disease (AD), yet has not become a reality. A critical challenge is the transplantation microenvironment, which impacts the therapeutic effect of stem cells. In AD brains, amyloid-beta (Aβ) peptides and inflammatory cytokines continuously poison the tissue microenvironment, leading to low survival of grafted cells and restricted efficacy. It is necessary to create a growth-supporting microenvironment for transplanted cells. Recent advances in AD studies suggest that the asparaginyl endopeptidase (AEP) is a potential intervention target for modifying pathological changes. We here chose APP/PS1 mice as an AD model and employed pharmacological inhibition of the AEP for one month to improve the brain microenvironment. Thereafter, we transplanted neural stem cells (NSCs) into the hippocampus and maintained therapy for one more month. We found that inhibition of AEPs resulted in a significant decrease of Aβ, TNF-α, IL-6 and IL-1β in their brains. In AD mice receiving NSC transplantation alone, the survival of NSCs was at a low level, while in combination with AEP inhibition pre-treatment the survival rate of engrafted cells was doubled. Within the 2-month treatment period, implantation of NSCs plus pre-inhibition of the AEP significantly enhanced neural plasticity of the hippocampus and rescued cognitive impairment. Neither NSC transplantation alone nor AEP inhibition alone achieved significant efficacy. In conclusion, pharmacological inhibition of the AEP ameliorated brain microenvironment of AD mice, and thus improved the survival and therapeutic efficacy of transplanted stem cells. Full article
(This article belongs to the Special Issue Alzheimer’s Disease: From Molecular Basis to Therapy 2.0)
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16 pages, 2070 KiB  
Article
Auditory or Audiovisual Stimulation Ameliorates Cognitive Impairment and Neuropathology in ApoE4 Knock-In Mice
by Harry Jung, Yeonkyeong Lee, Sang-Hwa Lee and Jong-Hee Sohn
Int. J. Mol. Sci. 2023, 24(2), 938; https://doi.org/10.3390/ijms24020938 - 4 Jan 2023
Cited by 4 | Viewed by 2049
Abstract
We hypothesized that auditory stimulation could reduce the progression of Alzheimer’s disease (AD), and that audiovisual stimulation could have additional effects through multisensory integration. We exposed 12 month old Apoetm1.1(APOE*4)Adiuj mice (a mouse model of sporadic AD) to auditory (A) or audiovisual [...] Read more.
We hypothesized that auditory stimulation could reduce the progression of Alzheimer’s disease (AD), and that audiovisual stimulation could have additional effects through multisensory integration. We exposed 12 month old Apoetm1.1(APOE*4)Adiuj mice (a mouse model of sporadic AD) to auditory (A) or audiovisual stimulation (AV) at 40 Hz for 14 days in a soundproof chamber system (no stimulation, N). Behavioral tests were performed before and after each session, and their brain tissues were assessed for amyloid-beta expression and apoptotic cell death, after 14 days. Furthermore, brain levels of acetylcholine and apoptosis-related proteins were analyzed. In the Y-maze test, the percentage relative alternation was significantly higher in group A than in group N mice. Amyloid-beta and TUNEL positivity in the hippocampal CA3 region was significantly lower in group A and group AV mice than in group N mice (p < 0.05). Acetylcholine levels were significantly higher in group A and group AV mice than in group N mice (p < 0.05). Compared to group N mice, expression of the proapoptotic proteins Bax and caspase-3 was lower in group A, and expression of the antiapoptotic protein Bcl-2 was higher in group AV. In a mouse model of early-stage sporadic AD, auditory or audiovisual stimulation improved cognitive performance and neuropathology. Full article
(This article belongs to the Special Issue Alzheimer’s Disease: From Molecular Basis to Therapy 2.0)
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14 pages, 2988 KiB  
Article
Effect of cx-DHED on Abnormal Glucose Transporter Expression Induced by AD Pathologies in the 5xFAD Mouse Model
by Jinho Kim, ShinWoo Kang and Keun-A Chang
Int. J. Mol. Sci. 2022, 23(18), 10602; https://doi.org/10.3390/ijms231810602 - 13 Sep 2022
Cited by 3 | Viewed by 1807
Abstract
Alzheimer’s disease (AD) is a form of dementia associated with abnormal glucose metabolism resulting from amyloid-beta (Aβ) plaques and intracellular neurofibrillary tau protein tangles. In a previous study, we confirmed that carboxy-dehydroevodiamine∙HCl (cx-DHED), a derivative of DHED, was effective at improving cognitive impairment [...] Read more.
Alzheimer’s disease (AD) is a form of dementia associated with abnormal glucose metabolism resulting from amyloid-beta (Aβ) plaques and intracellular neurofibrillary tau protein tangles. In a previous study, we confirmed that carboxy-dehydroevodiamine∙HCl (cx-DHED), a derivative of DHED, was effective at improving cognitive impairment and reducing phosphorylated tau levels and synaptic loss in an AD mouse model. However, the specific mechanism of action of cx-DHED is unclear. In this study, we investigated how the cx-DHED attenuates AD pathologies in the 5xFAD mouse model, focusing particularly on abnormal glucose metabolism. We analyzed behavioral changes and AD pathologies in mice after intraperitoneal injection of cx-DHED for 2 months. As expected, cx-DHED reversed memory impairment and reduced Aβ plaques and astrocyte overexpression in the brains of 5xFAD mice. Interestingly, cx-DHED reversed the abnormal expression of glucose transporters in the brains of 5xFAD mice. In addition, otherwise low O-GlcNac levels increased, and the overactivity of phosphorylated GSK-3β decreased in the brains of cx-DHED-treated 5xFAD mice. Finally, the reduction in synaptic proteins was found to also improve by treatment with cx-DHED. Therefore, we specifically demonstrated the protective effects of cx-DHED against AD pathologies and suggest that cx-DHED may be a potential therapeutic drug for AD. Full article
(This article belongs to the Special Issue Alzheimer’s Disease: From Molecular Basis to Therapy 2.0)
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Review

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22 pages, 1633 KiB  
Review
Comorbidity Genes of Alzheimer’s Disease and Type 2 Diabetes Associated with Memory and Cognitive Function
by Seong Beom Cho
Int. J. Mol. Sci. 2024, 25(4), 2211; https://doi.org/10.3390/ijms25042211 - 12 Feb 2024
Viewed by 1180
Abstract
Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) are comorbidities that result from the sharing of common genes. The molecular background of comorbidities can provide clues for the development of treatment and management strategies. Here, the common genes involved in the development [...] Read more.
Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) are comorbidities that result from the sharing of common genes. The molecular background of comorbidities can provide clues for the development of treatment and management strategies. Here, the common genes involved in the development of the two diseases and in memory and cognitive function are reviewed. Network clustering based on protein–protein interaction network identified tightly connected gene clusters that have an impact on memory and cognition among the comorbidity genes of AD and T2DM. Genes with functional implications were intensively reviewed and relevant evidence summarized. Gene information will be useful in the discovery of biomarkers and the identification of tentative therapeutic targets for AD and T2DM. Full article
(This article belongs to the Special Issue Alzheimer’s Disease: From Molecular Basis to Therapy 2.0)
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