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Alzheimer’s Disease: Pathogenesis, Diagnostics, and Treatment in the Early Stages

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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 (20 April 2023) | Viewed by 6263

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Special Issue Editor

Prof. Dr. Xiaochuan Wang

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Guest Editor

Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
Interests: the role of abnormal protein posttranslational modifications in Alzheimer’s disease (AD); drug screening based on AD molecules; AD model; AD diagnosis

Special Issue Information

Dear Colleagues,

Alzheimer’s disease (AD), being the number one in terms of dementia burden, is an insidious age-related neurodegenerative disease and is presently considered as a global public health threat. Its main histological hallmarks are the Aβ senile plaques and the P-tau neurofibrillary tangles, while clinically it is marked by a progressive cognitive decline that reflects the underlying synaptic loss and neurodegeneration. Many of the drug therapies targeting the two pathological hallmarks namely Aβ and P-tau have been proven futile. This is probably attributed to the initiation of therapy at a stage where cognitive alterations are already obvious. In other words, the underlying neuropathological changes are at a stage where these drugs lack any therapeutic value in reversing the damage. Therefore, there is an urgent need to start treatment in the very early stage where these changes can be reversed and hence, early diagnosis is of primordial importance based on the Pathogenesis of AD.

The present Special Issue aims to provide an overview of the current research on the promising significance, etiopathogenesis, therapeutics, and prevention of AD.

Prof. Yiyuan Xi and Associate Prof. Jian Bao from Jianghan University, Prof. Jianlan Gu from Nantong University also made great contributions to editing this special issue.

Prof. Dr. Xiaochuan Wang
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
mechanism
diagnostics
treatment

Published Papers (3 papers)

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Research

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23 pages, 4456 KiB

Open AccessArticle

HIF-1α Causes LCMT1/PP2A Deficiency and Mediates Tau Hyperphosphorylation and Cognitive Dysfunction during Chronic Hypoxia

by Ling Lei, Jun Feng, Gang Wu, Zhen Wei, Jian-Zhi Wang, Bin Zhang, Rong Liu, Fei Liu, Xiaochuan Wang and Hong-Lian Li

Int. J. Mol. Sci. 2022, 23(24), 16140; https://doi.org/10.3390/ijms232416140 - 17 Dec 2022

Cited by 11 | Viewed by 2122

Abstract

Chronic hypoxia is a risk factor for Alzheimer’s disease (AD), and the neurofibrillary tangle (NFT) formed by hyperphosphorylated tau is one of the two major pathological changes in AD. However, the effect of chronic hypoxia on tau phosphorylation and its mechanism remains unclear. In this study, we investigated the role of HIF-1α (the functional subunit of hypoxia-inducible factor 1) in tau pathology. It was found that in Sprague-Dawley (SD) rats, global hypoxia (10% O₂, 6 h per day) for one month induced cognitive impairments. Meanwhile it induced HIF-1α increase, tau hyperphosphorylation, and protein phosphatase 2A (PP2A) deficiency with leucine carboxyl methyltransferase 1(LCMT1, increasing PP2A activity) decrease in the rats’ hippocampus. The results were replicated by hypoxic treatment in primary hippocampal neurons and C6/tau cells (rat C6 glioma cells stably expressing human full-length tau441). Conversely, HIF-1α silencing impeded the changes induced by hypoxia, both in primary neurons and SD rats. The result of dual luciferase assay proved that HIF-1α acted as a transcription factor of LCMT1. Unexpectedly, HIF-1α decreased the protein level of LCMT1. Further study uncovered that both overexpression of HIF-1α and hypoxia treatment resulted in a sizable degradation of LCMT1 via the autophagy–-lysosomal pathway. Together, our data strongly indicated that chronic hypoxia upregulates HIF-1α, which obviously accelerated LCMT1 degradation, thus counteracting its transcriptional expression. The increase in HIF-1α decreases PP2A activity, finally resulting in tau hyperphosphorylation and cognitive dysfunction. Lowering HIF-1α in chronic hypoxia conditions may be useful in AD prevention. Full article

(This article belongs to the Special Issue Alzheimer’s Disease: Pathogenesis, Diagnostics, and Treatment in the Early Stages)

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16 pages, 4393 KiB

Open AccessArticle

Impact of Amyloid Pathology in Mild Cognitive Impairment Subjects: The Longitudinal Cognition and Surface Morphometry Data

by Hsin-I Chang, Shih-Wei Hsu, Zih-Kai Kao, Chen-Chang Lee, Shu-Hua Huang, Ching-Heng Lin, Mu-N Liu and Chiung-Chih Chang

Int. J. Mol. Sci. 2022, 23(23), 14635; https://doi.org/10.3390/ijms232314635 - 23 Nov 2022

Cited by 3 | Viewed by 1631

Abstract

The amyloid framework forms the central medical theory related to Alzheimer disease (AD), and the in vivo demonstration of amyloid positivity is essential for diagnosing AD. On the basis of a longitudinal cohort design, the study investigated clinical progressive patterns by obtaining cognitive and structural measurements from a group of patients with amnestic mild cognitive impairment (MCI); the measurements were classified by the positivity (Aβ+) or absence (Aβ−) of the amyloid biomarker. We enrolled 185 patients (64 controls, 121 patients with MCI). The patients with MCI were classified into two groups on the basis of their [¹⁸F]flubetaben or [¹⁸F]florbetapir amyloid positron-emission tomography scan (Aβ+ vs. Aβ−, 67 vs. 54 patients) results. Data from annual cognitive measurements and three-dimensional T1 magnetic resonance imaging scans were used for between-group comparisons. To obtain longitudinal cognitive test scores, generalized estimating equations were applied. A linear mixed effects model was used to compare the time effect of cortical thickness degeneration. The cognitive decline trajectory of the Aβ+ group was obvious, whereas the Aβ− and control groups did not exhibit a noticeable decline over time. The group effects of cortical thickness indicated decreased entorhinal cortex in the Aβ+ group and supramarginal gyrus in the Aβ− group. The topology of neurodegeneration in the Aβ− group was emphasized in posterior cortical regions. A comparison of the changes in the Aβ+ and Aβ− groups over time revealed a higher rate of cortical thickness decline in the Aβ+ group than in the Aβ− group in the default mode network. The Aβ+ and Aβ− groups experienced different APOE ε4 effects. For cortical–cognitive correlations, the regions associated with cognitive decline in the Aβ+ group were mainly localized in the perisylvian and anterior cingulate regions. By contrast, the degenerative topography of Aβ− MCI was scattered. The memory learning curves, cognitive decline patterns, and cortical degeneration topographies of the two MCI groups were revealed to be different, suggesting a difference in pathophysiology. Longitudinal analysis may help to differentiate between these two MCI groups if biomarker access is unavailable in clinical settings. Full article

(This article belongs to the Special Issue Alzheimer’s Disease: Pathogenesis, Diagnostics, and Treatment in the Early Stages)

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Review

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17 pages, 1105 KiB

Open AccessReview

The Importance of Subjective Cognitive Decline Recognition and the Potential of Molecular and Neurophysiological Biomarkers—A Systematic Review

by Janina Ulbl and Martin Rakusa

Int. J. Mol. Sci. 2023, 24(12), 10158; https://doi.org/10.3390/ijms241210158 - 15 Jun 2023

Cited by 2 | Viewed by 1955

Abstract

Subjective cognitive decline (SCD) and mild cognitive impairment (MCI) are early stages of Alzheimer’s disease (AD). Neurophysiological markers such as electroencephalography (EEG) and event-related potential (ERP) are emerging as alternatives to traditional molecular and imaging markers. This paper aimed to review the literature on EEG and ERP markers in individuals with SCD. We analysed 30 studies that met our criteria, with 17 focusing on resting-state or cognitive task EEG, 11 on ERPs, and two on both EEG and ERP parameters. Typical spectral changes were indicative of EEG rhythm slowing and were associated with faster clinical progression, lower education levels, and abnormal cerebrospinal fluid biomarkers profiles. Some studies found no difference in ERP components between SCD subjects, controls, or MCI, while others reported lower amplitudes in the SCD group compared to controls. Further research is needed to explore the prognostic value of EEG and ERP in relation to molecular markers in individuals with SCD. Full article

(This article belongs to the Special Issue Alzheimer’s Disease: Pathogenesis, Diagnostics, and Treatment in the Early Stages)

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