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Molecular Mechanisms of Alzheimer’s Disease and Brain Tolerance

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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 (30 November 2021) | Viewed by 16534

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Special Issue Editor

Dr. Sónia C. Correia

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Guest Editor

CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
Interests: Alzheimer's disease; preconditioning; mitochondria; HIF-1alpha
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is well-known that Alzheimer’s disease (AD) is the main cause of dementia and the most prevalent brain disorder in the elderly, being considered a major public health concern worldwide. More than 100 years after the first case report, AD is still an incurable disease with no effective disease-modifying therapies, in part because the etiopathogenesis of this devastating neurogenerative disease remains elusive. In this sense, the Special Issue “Molecular Mechanisms of Alzheimer’s Disease and Brain Tolerance” aims to gather the most recent advances in the field to provide a more comprehensive picture of the molecular basis underlying the selective neuronal degeneration and loss in AD. Furthermore, this Special Issue also intends to describe the endogenous adaptative and pro-survival mechanisms behind brain tolerance (hormesis/conditioning) as promising targets to counteract AD symptomatology and neuropathology in a timely manner.

This Special Issue welcomes the submission of original research or review articles focusing on the cellular and molecular events that contribute to the onset and progression of AD (i.e., vascular dysfunction, brain hypometabolism, mitochondrial dysfunction and oxidative stress, synaptic failure, neuroinflammation, gut dysbiosis, among others) and to brain tolerance against injury.

Dr. Sónia C. Correia
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
brain metabolism
endoplasmic reticulum
hormesis
microbiome
mitochondria
neuroinflammation
oxidative stress
synapses
vascular component

Published Papers (5 papers)

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Research

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23 pages, 4793 KiB

Open AccessArticle

PEAβ Triggers Cognitive Decline and Amyloid Burden in a Novel Mouse Model of Alzheimer’s Disease

by Luana Cristina Camargo, Michael Schöneck, Nivethini Sangarapillai, Dominik Honold, N. Jon Shah, Karl-Josef Langen, Dieter Willbold, Janine Kutzsche, Sarah Schemmert and Antje Willuweit

Int. J. Mol. Sci. 2021, 22(13), 7062; https://doi.org/10.3390/ijms22137062 - 30 Jun 2021

Cited by 3 | Viewed by 2248

Abstract

Understanding the physiopathology of Alzheimer’s disease (AD) has improved substantially based on studies of mouse models mimicking at least one aspect of the disease. Many transgenic lines have been established, leading to amyloidosis but lacking neurodegeneration. The aim of the current study was to generate a novel mouse model that develops neuritic plaques containing the aggressive pyroglutamate modified amyloid-β (pEAβ) species in the brain. The TAPS line was developed by intercrossing of the pEAβ-producing TBA2.1 mice with the plaque-developing line APPswe/PS1ΔE9. The phenotype of the new mouse line was characterized using immunostaining, and different cognitive and general behavioral tests. In comparison to the parental lines, TAPS animals developed an earlier onset of pathology and increased plaque load, including striatal pEAβ-positive neuritic plaques, and enhanced neuroinflammation. In addition to abnormalities in general behavior, locomotion, and exploratory behavior, TAPS mice displayed cognitive deficits in a variety of tests that were most pronounced in the fear conditioning paradigm and in spatial learning in comparison to the parental lines. In conclusion, the combination of a pEAβ- and a plaque-developing mouse model led to an accelerated amyloid pathology and cognitive decline in TAPS mice, qualifying this line as a novel amyloidosis model for future studies. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Alzheimer’s Disease and Brain Tolerance)

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Graphical abstract

18 pages, 3288 KiB

Open AccessArticle

In Vitro and In Vivo Efficacies of the Linear and the Cyclic Version of an All-d-Enantiomeric Peptide Developed for the Treatment of Alzheimer’s Disease

by Sarah Schemmert, Luana Cristina Camargo, Dominik Honold, Ian Gering, Janine Kutzsche, Antje Willuweit and Dieter Willbold

Int. J. Mol. Sci. 2021, 22(12), 6553; https://doi.org/10.3390/ijms22126553 - 18 Jun 2021

Cited by 7 | Viewed by 1972

Abstract

Multiple sources of evidence suggest that soluble amyloid β (Aβ)-oligomers are responsible for the development and progression of Alzheimer’s disease (AD). In order to specifically eliminate these toxic Aβ-oligomers, our group has developed a variety of all-d-peptides over the past years. One of them, RD2, has been intensively studied and showed such convincing in vitro and in vivo properties that it is currently in clinical trials. In order to further optimize the compounds and to elucidate the characteristics of therapeutic d-peptides, several rational drug design approaches have been performed. Two of these d-peptides are the linear tandem (head-to-tail) d-peptide RD2D3 and its cyclized form cRD2D3. Tandemization and cyclization should result in an increased in vitro potency and increase pharmacokinetic properties, especially crossing the blood–brain-barrier. In comparison, cRD2D3 showed a superior pharmacokinetic profile to RD2D3. This fact suggests that higher efficacy can be achieved in vivo at equally administered concentrations. To prove this hypothesis, we first established the in vitro profile of both d-peptides here. Subsequently, we performed an intraperitoneal treatment study. This study failed to provide evidence that cRD2D3 is superior to RD2D3 in vivo as in some tests cRD2D3 failed to show equal or higher efficacy. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Alzheimer’s Disease and Brain Tolerance)

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20 pages, 3124 KiB

Open AccessArticle

Key Disease Mechanisms Linked to Alzheimer’s Disease in the Entorhinal Cortex

by Virginie Bottero, Dallen Powers, Ashna Yalamanchi, James P. Quinn and Judith A. Potashkin

Int. J. Mol. Sci. 2021, 22(8), 3915; https://doi.org/10.3390/ijms22083915 - 10 Apr 2021

Cited by 18 | Viewed by 3376

Abstract

Alzheimer’s disease (AD) is a chronic, neurodegenerative brain disorder affecting millions of Americans that is expected to increase in incidence with the expanding aging population. Symptomatic AD patients show cognitive decline and often develop neuropsychiatric symptoms due to the accumulation of insoluble proteins that produce plaques and tangles seen in the brain at autopsy. Unexpectedly, some clinically normal individuals also show AD pathology in the brain at autopsy (asymptomatic AD, AsymAD). In this study, SWItchMiner software was used to identify key switch genes in the brain’s entorhinal cortex that lead to the development of AD or disease resilience. Seventy-two switch genes were identified that are differentially expressed in AD patients compared to healthy controls. These genes are involved in inflammation, platelet activation, and phospholipase D and estrogen signaling. Peroxisome proliferator-activated receptor γ (PPARG), zinc-finger transcription factor (YY1), sterol regulatory element-binding transcription factor 2 (SREBF2), and early growth response 1 (EGR1) were identified as transcription factors that potentially regulate switch genes in AD. Comparing AD patients to AsymAD individuals revealed 51 switch genes; PPARG as a potential regulator of these genes, and platelet activation and phospholipase D as critical signaling pathways. Chemical–protein interaction analysis revealed that valproic acid is a therapeutic agent that could prevent AD from progressing. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Alzheimer’s Disease and Brain Tolerance)

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Review

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32 pages, 2017 KiB

Open AccessReview

Fatty Acids: An Insight into the Pathogenesis of Neurodegenerative Diseases and Therapeutic Potential

by Diego Julián Vesga-Jiménez, Cynthia Martin, George E. Barreto, Andrés Felipe Aristizábal-Pachón, Andrés Pinzón and Janneth González

Int. J. Mol. Sci. 2022, 23(5), 2577; https://doi.org/10.3390/ijms23052577 - 25 Feb 2022

Cited by 28 | Viewed by 4111

Abstract

One of the most common lipids in the human body is palmitic acid (PA), a saturated fatty acid with essential functions in brain cells. PA is used by cells as an energy source, besides being a precursor of signaling molecules and protein tilting across the membrane. Although PA plays physiological functions in the brain, its excessive accumulation leads to detrimental effects on brain cells, causing lipotoxicity. This mechanism involves the activation of toll-like receptors (TLR) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways, with the consequent release of pro-inflammatory cytokines, increased production of reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, and autophagy impairment. Importantly, some of the cellular changes induced by PA lead to an augmented susceptibility to the development of Alzheimer’s and Parkinson´s diseases. Considering the complexity of the response to PA and the intrinsic differences of the brain, in this review, we provide an overview of the molecular and cellular effects of PA on different brain cells and their possible relationships with neurodegenerative diseases (NDs). Furthermore, we propose the use of other fatty acids, such as oleic acid or linoleic acid, as potential therapeutic approaches against NDs, as these fatty acids can counteract PA’s negative effects on cells. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Alzheimer’s Disease and Brain Tolerance)

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27 pages, 1266 KiB

Open AccessReview

A Fundamental Role for Oxidants and Intracellular Calcium Signals in Alzheimer’s Pathogenesis—And How a Comprehensive Antioxidant Strategy May Aid Prevention of This Disorder

by Mark F. McCarty, James J. DiNicolantonio and Aaron Lerner

Int. J. Mol. Sci. 2021, 22(4), 2140; https://doi.org/10.3390/ijms22042140 - 21 Feb 2021

Cited by 11 | Viewed by 3914

Abstract

Oxidative stress and increased cytoplasmic calcium are key mediators of the detrimental effects on neuronal function and survival in Alzheimer’s disease (AD). Pathways whereby these perturbations arise, and then prevent dendritic spine formation, promote tau hyperphosphorylation, further amplify amyloid β generation, and induce neuronal apoptosis, are described. A comprehensive program of nutraceutical supplementation, comprised of the NADPH oxidase inhibitor phycocyanobilin, phase two inducers, the mitochondrial antioxidant astaxanthin, and the glutathione precursor N-acetylcysteine, may have important potential for antagonizing the toxic effects of amyloid β on neurons and thereby aiding prevention of AD. Moreover, nutraceutical antioxidant strategies may oppose the adverse impact of amyloid β oligomers on astrocyte clearance of glutamate, and on the ability of brain capillaries to export amyloid β monomers/oligomers from the brain. Antioxidants, docosahexaenoic acid (DHA), and vitamin D, have potential for suppressing microglial production of interleukin-1β, which potentiates the neurotoxicity of amyloid β. Epidemiology suggests that a health-promoting lifestyle, incorporating a prudent diet, regular vigorous exercise, and other feasible measures, can cut the high risk for AD among the elderly by up to 60%. Conceivably, complementing such lifestyle measures with long-term adherence to the sort of nutraceutical regimen outlined here may drive down risk for AD even further. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Alzheimer’s Disease and Brain Tolerance)

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