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Molecular Mechanism of Alzheimer's Disease IV
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Molecular Mechanism of Alzheimer's Disease IV

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 (31 December 2023) | Viewed by 3612

Special Issue Editor

Prof. Dr. Ludwig Aigner

E-Mail Website
Guest Editor
Paracelsus Medizinische Privatuniversitat, Institute of Molecular Regenerative Medicine, Salzburg, Austria
Interests: neuroregeneration; neurogenesis; neuroinflammation; regenerative medicine; stem cells

Special Issue Information

Dear Colleagues,

This Special Issue is the fourth volume in a series of Special Issues titled "Molecular Mechanism of Alzheimer's Disease", "Molecular Mechanism of Alzheimer's Disease II", and “Molecular Mechanism of Alzheimer's Disease III”. Alzheimer’s disease (AD) is an age-related neurological disease that affects tens of millions of people and their carers worldwide. Hallmark features of AD include plaques composed of amyloid beta, as well as neurofibrillary tangles of tau protein. However, despite more than a century of research, the cause of AD remains inconclusive. The roles of amyloid beta and tau are being investigated, and other causes of AD are now under consideration. The contributions of researchers, model organisms, and various hypotheses will be examined in this Special Issue.

Prof. Dr. Ludwig Aigner
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
  • amyloid beta
  • brain cholesterol
  • brain microbes
  • neurofibrillary tangles
  • neurodegeneration
  • neuroinflammation
  • oxidative stress
  • proteostasis
  • tau
  • type 3 diabetes

Published Papers (2 papers)

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Research

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11 pages, 965 KiB  
Article
Alzheimer’s Precision Neurology: Epigenetics of Cytochrome P450 Genes in Circulating Cell-Free DNA for Disease Prediction and Mechanism
by Ray O. Bahado-Singh, Sangeetha Vishweswaraiah, Onur Turkoglu, Stewart F. Graham and Uppala Radhakrishna
Int. J. Mol. Sci. 2023, 24(3), 2876; https://doi.org/10.3390/ijms24032876 - 2 Feb 2023
Cited by 3 | Viewed by 2205
Abstract
Precision neurology combines high-throughput technologies and statistical modeling to identify novel disease pathways and predictive biomarkers in Alzheimer’s disease (AD). Brain cytochrome P450 (CYP) genes are major regulators of cholesterol, sex hormone, and xenobiotic metabolism, and they could play important roles in neurodegenerative [...] Read more.
Precision neurology combines high-throughput technologies and statistical modeling to identify novel disease pathways and predictive biomarkers in Alzheimer’s disease (AD). Brain cytochrome P450 (CYP) genes are major regulators of cholesterol, sex hormone, and xenobiotic metabolism, and they could play important roles in neurodegenerative disorders. Increasing evidence suggests that epigenetic factors contribute to AD development. We evaluated cytosine (‘CpG’)-based DNA methylation changes in AD using circulating cell-free DNA (cfDNA), to which neuronal cells are known to contribute. We investigated CYP-based mechanisms for AD pathogenesis and epigenetic biomarkers for disease detection. We performed a case–control study using 25 patients with AD and 23 cognitively healthy controls using the cfDNA of CYP genes. We performed a logistic regression analysis using the MetaboAnalyst software computer program and a molecular pathway analysis based on epigenetically altered CYP genes using the Cytoscape program. We identified 130 significantly (false discovery rate correction q-value < 0.05) differentially methylated CpG sites within the CYP genes. The top two differentially methylated genes identified were CYP51A1 and CYP2S1. The significant molecular pathways that were perturbed in AD cfDNA were (i) androgen and estrogen biosynthesis and metabolism, (ii) C21 steroid hormone biosynthesis and metabolism, and (iii) arachidonic acid metabolism. Existing evidence suggests a potential role of each of these biochemical pathways in AD pathogenesis. Next, we randomly divided the study group into discovery and validation sub-sets, each consisting of patients with AD and control patients. Regression models for AD prediction based on CYP CpG methylation markers were developed in the discovery or training group and tested in the independent validation group. The CYP biomarkers achieved a high predictive accuracy. After a 10-fold cross-validation, the combination of cg17852385/cg23101118 + cg14355428/cg22536554 achieved an AUC (95% CI) of 0.928 (0.787~1.00), with 100% sensitivity and 92.3% specificity for AD detection in the discovery group. The performance remained high in the independent validation or test group, achieving an AUC (95% CI) of 0.942 (0.905~0.979) with a 90% sensitivity and specificity. Our findings suggest that the epigenetic modification of CYP genes may play an important role in AD pathogenesis and that circulating CYP-based cfDNA biomarkers have the potential to accurately and non-invasively detect AD. Full article
(This article belongs to the Special Issue Molecular Mechanism of Alzheimer's Disease IV)
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Review

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12 pages, 1285 KiB  
Review
Cerebrospinal and Blood Biomarkers in Alzheimer’s Disease: Did Mild Cognitive Impairment Definition Affect Their Clinical Usefulness?
by Giulia Bivona, Matilda Iemmolo and Giulio Ghersi
Int. J. Mol. Sci. 2023, 24(23), 16908; https://doi.org/10.3390/ijms242316908 - 29 Nov 2023
Cited by 2 | Viewed by 1090
Abstract
Despite Alzheimer’s Disease (AD) being known from the times of Alois Alzheimer, who lived more than one century ago, many aspects of the disease are still obscure, including the pathogenesis, the clinical spectrum definition, and the therapeutic approach. Well-established biomarkers for AD come [...] Read more.
Despite Alzheimer’s Disease (AD) being known from the times of Alois Alzheimer, who lived more than one century ago, many aspects of the disease are still obscure, including the pathogenesis, the clinical spectrum definition, and the therapeutic approach. Well-established biomarkers for AD come from the histopathological hallmarks of the disease, which are Aβ and phosphorylated Tau protein aggregates. Consistently, cerebrospinal fluid (CSF) Amyloid β (Aβ) and phosphorylated Tau level measurements are currently used to detect AD presence. However, two central biases affect these biomarkers. Firstly, incomplete knowledge of the pathogenesis of diseases legitimates the search for novel molecules that, reasonably, could be expressed by neurons and microglia and could be detected in blood simpler and earlier than the classical markers and in a higher amount. Further, studies have been performed to evaluate whether CSF biomarkers can predict AD onset in Mild Cognitive Impairment (MCI) patients. However, the MCI definition has changed over time. Hence, the studies on MCI patients seem to be biased at the beginning due to the imprecise enrollment and heterogeneous composition of the miscellaneous MCI subgroup. Plasma biomarkers and novel candidate molecules, such as microglia biomarkers, have been tentatively investigated and could represent valuable targets for diagnosing and monitoring AD. Also, novel AD markers are urgently needed to identify molecular targets for treatment strategies. This review article summarizes the main CSF and blood AD biomarkers, underpins their advantages and flaws, and mentions novel molecules that can be used as potential biomarkers for AD. Full article
(This article belongs to the Special Issue Molecular Mechanism of Alzheimer's Disease IV)
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