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Dementia: From Molecular Pathophysiology to Novel Therapeutic Approaches
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Dementia: From Molecular Pathophysiology to Novel Therapeutic Approaches

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: 30 July 2024 | Viewed by 6451

Special Issue Editor

Dr. Camilla Ferrari

E-Mail Website
Guest Editor
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, 50134 Florence, Italy
Interests: dementia; neurodegenerative disorders; Alzheimer’s disease; Huntington disease; ataxia; genetics

Special Issue Information

Dear Colleagues,

Dementia is a serious health and economic problem worldwide. Despite many efforts, there are not effective treatments to prevent or cure dementia. Neurodegenerative dementias are characterized by the accumulation of specific proteins, but they also share common processes such as neuroinflammation, vascular damage, and oxidative stress. The cooperation of all these mechanisms determines the onset and the progression of such diseases. Therefore, modern therapies are moving from monocentric to multitarget approaches. Recently, gene editing has been of rising interest, both as potential treatment and as technique to study pathophysiological cascades. Another crucial point in dementia research is the lack of concordance between animal or cellular models with human studies, especially in terms of drug efficacy.

This Special Issue aims to cover every necessary step in the process of developing new drugs in the field of neurodegenerative dementias, including:

  1. Identifying models that faithfully reproduce human pathologies;
  2. Expanding knowledge on pathophysiological mechanisms and their interconnections in determining the onset and progression of dementias;
  3. Screening for potential new drugs.

Experimental studies in in vitro or in vivo models and biomolecular experiments in clinical settings are both welcome for consideration.

Dr. Camilla Ferrari
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

  • dementia
  • Alzheimer’s disease
  • fronto-temporal dementia
  • parkinson-dementia
  • Huntington disease
  • neurodegenerative diseases
  • vascular dementia
  • neuroinflammation
  • proteinopathy
  • oxidative stress
  • gene editing
  • animal model
  • cellular model
  • therapies

Published Papers (2 papers)

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Research

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12 pages, 1406 KiB  
Article
Ceramides Mediate Insulin-Induced Impairments in Cerebral Mitochondrial Bioenergetics in ApoE4 Mice
by Sheryl T. Carr, Erin R. Saito, Chase M. Walton, Jeremy Y. Saito, Cameron M. Hanegan, Cali E. Warren, Annie M. Trumbull and Benjamin T. Bikman
Int. J. Mol. Sci. 2023, 24(23), 16635; https://doi.org/10.3390/ijms242316635 - 23 Nov 2023
Cited by 1 | Viewed by 3518
Abstract
Alzheimer’s disease (AD) is the most common form of neurodegenerative disease worldwide. A large body of work implicates insulin resistance in the development and progression of AD. Moreover, impairment in mitochondrial function, a common symptom of insulin resistance, now represents a fundamental aspect [...] Read more.
Alzheimer’s disease (AD) is the most common form of neurodegenerative disease worldwide. A large body of work implicates insulin resistance in the development and progression of AD. Moreover, impairment in mitochondrial function, a common symptom of insulin resistance, now represents a fundamental aspect of AD pathobiology. Ceramides are a class of bioactive sphingolipids that have been hypothesized to drive insulin resistance. Here, we describe preliminary work that tests the hypothesis that hyperinsulinemia pathologically alters cerebral mitochondrial function in AD mice via accrual of the ceramides. Homozygous male and female ApoE4 mice, an oft-used model of AD research, were given chronic injections of PBS (control), insulin, myriocin (an inhibitor of ceramide biosynthesis), or insulin and myriocin over four weeks. Cerebral ceramide content was assessed using liquid chromatography–mass spectrometry. Mitochondrial oxygen consumption rates were measured with high-resolution respirometry, and H2O2 emissions were quantified via biochemical assays on brain tissue from the cerebral cortex. Significant increases in brain ceramides and impairments in brain oxygen consumption were observed in the insulin-treated group. These hyperinsulinemia-induced impairments in mitochondrial function were reversed with the administration of myriocin. Altogether, these data demonstrate a causative role for insulin in promoting brain ceramide accrual and subsequent mitochondrial impairments that may be involved in AD expression and progression. Full article
(This article belongs to the Special Issue Dementia: From Molecular Pathophysiology to Novel Therapeutic Approaches)
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Review

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18 pages, 1952 KiB  
Review
The Single Toxin Origin of Alzheimer’s Disease and Other Neurodegenerative Disorders Enables Targeted Approach to Treatment and Prevention
by Martin Tolar, John A. Hey, Aidan Power and Susan Abushakra
Int. J. Mol. Sci. 2024, 25(5), 2727; https://doi.org/10.3390/ijms25052727 - 27 Feb 2024
Viewed by 2361
Abstract
New data suggest that the aggregation of misfolded native proteins initiates and drives the pathogenic cascade that leads to Alzheimer’s disease (AD) and other age-related neurodegenerative disorders. We propose a unifying single toxin theory of brain neurodegeneration that identifies new targets and approaches [...] Read more.
New data suggest that the aggregation of misfolded native proteins initiates and drives the pathogenic cascade that leads to Alzheimer’s disease (AD) and other age-related neurodegenerative disorders. We propose a unifying single toxin theory of brain neurodegeneration that identifies new targets and approaches to the development of disease-modifying treatments. An extensive body of genetic evidence suggests soluble aggregates of beta-amyloid (Aβ) as the primary neurotoxin in the pathogenesis of AD. New insights from fluid biomarkers, imaging, and clinical studies provide further evidence for the decisive impact of toxic Aβ species in the initiation and progression of AD. Understanding the distinct roles of soluble and insoluble amyloid aggregates on AD pathogenesis has been the key missing piece of the Alzheimer’s puzzle. Data from clinical trials with anti-amyloid agents and recent advances in the diagnosis of AD demonstrate that the driving insult in biologically defined AD is the neurotoxicity of soluble Aβ aggregates, called oligomers and protofibrils, rather than the relatively inert insoluble mature fibrils and amyloid plaques. Amyloid oligomers appear to be the primary factor causing the synaptic impairment, neuronal stress, spreading of tau pathology, and eventual cell death that lead to the clinical syndrome of AD dementia. All other biochemical effects and neurodegenerative changes in the brain that are observed in AD are a response to or a downstream effect of this initial toxic insult by oligomers. Other neurodegenerative disorders follow a similar pattern of pathogenesis, in which normal brain proteins with important biological functions become trapped in the aging brain due to impaired clearance and then misfold and aggregate into neurotoxic species that exhibit prion-like behavior. These aggregates then spread through the brain and cause disease-specific neurodegeneration. Targeting the inhibition of this initial step in neurodegeneration by blocking the misfolding and aggregation of healthy proteins has the potential to slow or arrest disease progression, and if treatment is administered early in the course of AD and other neurodegenerative disorders, it may delay or prevent the onset of clinical symptoms. Full article
(This article belongs to the Special Issue Dementia: From Molecular Pathophysiology to Novel Therapeutic Approaches)
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