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Molecular Mechanisms of Brain Aging and Alzheimer’s Disease
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Molecular Mechanisms of Brain Aging and Alzheimer’s Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 October 2023) | Viewed by 15020

Special Issue Editor

Dr. Salvatore Oddo

E-Mail Website
Guest Editor
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d’Alcontres, 31, 98168 Messina, Italy
Interests: Alzheimer's disease

Special Issue Information

Dear Colleagues,

Aging is the major risk factor for several neurodegenerative diseases, including Alzheimer’s disease (AD). Even in the rare case in which AD is triggered by an autosomal mutation in the APP or PS1 genes, the disease develops as a function of age. Despite this evidence, more needs to be done to unveil the molecular link between brain aging and AD.

The aging population represents the fastest-growing segment of our society. To this end, it is estimated that if nothing is done to stop or prevent the progression of AD, the incidence of the disease will greatly increase worldwide over the next 10 years. Unfortunately, recently, several promising clinical trials have failed. While different reasons may account for these negative results, perhaps it is time to go back to the drawing board and focus on the molecular mechanisms underlying the pathogenic processes underlying the onset and progression of AD and its relation to the aging brain: from the synaptic dysfunction to the accumulation of Aβ and tau, from microglia activation to neuronal death. A better understanding of the molecular changes underlying these pathogenic events may unveil novel or simply overlooked therapeutic targets.

Dr. Salvatore Oddo
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
  • APP
  • tau
  • Abeta
  • aging

Published Papers (5 papers)

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Review

22 pages, 795 KiB  
Review
Re-Arranging the Puzzle between the Amyloid-Beta and Tau Pathology: An APP-Centric Approach
by Florence Haut, Elentina K. Argyrousi and Ottavio Arancio
Int. J. Mol. Sci. 2024, 25(1), 259; https://doi.org/10.3390/ijms25010259 - 23 Dec 2023
Viewed by 1053
Abstract
After several years of research in the field of Alzheimer’s disease (AD), it is still unclear how amyloid-beta (Aβ) and Tau, two key hallmarks of the disease, mediate the neuropathogenic events that lead to AD. Current data challenge the “Amyloid Cascade Hypothesis” that [...] Read more.
After several years of research in the field of Alzheimer’s disease (AD), it is still unclear how amyloid-beta (Aβ) and Tau, two key hallmarks of the disease, mediate the neuropathogenic events that lead to AD. Current data challenge the “Amyloid Cascade Hypothesis” that has prevailed in the field of AD, stating that Aβ precedes and triggers Tau pathology that will eventually become the toxic entity in the progression of the disease. This perspective also led the field of therapeutic approaches towards the development of strategies that target Aβ or Tau. In the present review, we discuss recent literature regarding the neurotoxic role of both Aβ and Tau in AD, as well as their physiological function in the healthy brain. Consequently, we present studies suggesting that Aβ and Tau act independently of each other in mediating neurotoxicity in AD, thereafter, re-evaluating the “Amyloid Cascade Hypothesis” that places Tau pathology downstream of Aβ. More recent studies have confirmed that both Aβ and Tau could propagate the disease and induce synaptic and memory impairments via the amyloid precursor protein (APP). This finding is not only interesting from a mechanistic point of view since it provides better insights into the AD pathogenesis but also from a therapeutic point of view since it renders APP a common downstream effector for both Aβ and Tau. Subsequently, therapeutic strategies that act on APP might provide a more viable and physiologically relevant approach for targeting AD. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Brain Aging and Alzheimer’s Disease)
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24 pages, 1142 KiB  
Review
Potential Implications of miRNAs in the Pathogenesis, Diagnosis, and Therapeutics of Alzheimer’s Disease
by Long Wang, Xindong Shui, Yuelin Diao, Duoting Chen, Ying Zhou and Tae Ho Lee
Int. J. Mol. Sci. 2023, 24(22), 16259; https://doi.org/10.3390/ijms242216259 - 13 Nov 2023
Cited by 5 | Viewed by 2183
Abstract
Alzheimer’s disease (AD) is a complex multifactorial disorder that poses a substantial burden on patients, caregivers, and society. Considering the increased aging population and life expectancy, the incidence of AD will continue to rise in the following decades. However, the molecular pathogenesis of [...] Read more.
Alzheimer’s disease (AD) is a complex multifactorial disorder that poses a substantial burden on patients, caregivers, and society. Considering the increased aging population and life expectancy, the incidence of AD will continue to rise in the following decades. However, the molecular pathogenesis of AD remains controversial, superior blood-based biomarker candidates for early diagnosis are still lacking, and effective therapeutics to halt or slow disease progression are urgently needed. As powerful genetic regulators, microRNAs (miRNAs) are receiving increasing attention due to their implications in the initiation, development, and theranostics of various diseases, including AD. In this review, we summarize miRNAs that directly target microtubule-associated protein tau (MAPT), amyloid precursor protein (APP), and β-site APP-cleaving enzyme 1 (BACE1) transcripts and regulate the alternative splicing of tau and APP. We also discuss related kinases, such as glycogen synthase kinase (GSK)-3β, cyclin-dependent kinase 5 (CDK5), and death-associated protein kinase 1 (DAPK1), as well as apolipoprotein E, that are directly targeted by miRNAs to control tau phosphorylation and amyloidogenic APP processing leading to Aβ pathologies. Moreover, there is evidence of miRNA-mediated modulation of inflammation. Furthermore, circulating miRNAs in the serum or plasma of AD patients as noninvasive biomarkers with diagnostic potential are reviewed. In addition, miRNA-based therapeutics optimized with nanocarriers or exosomes as potential options for AD treatment are discussed. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Brain Aging and Alzheimer’s Disease)
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13 pages, 1104 KiB  
Review
The Role of miR-128 in Neurodegenerative Diseases
by Marika Lanza, Salvatore Cuzzocrea, Salvatore Oddo, Emanuela Esposito and Giovanna Casili
Int. J. Mol. Sci. 2023, 24(7), 6024; https://doi.org/10.3390/ijms24076024 - 23 Mar 2023
Cited by 3 | Viewed by 2235
Abstract
Several neurodegenerative disorders are characterized by the accumulation of misfolded proteins and are collectively known as proteinopathies. Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD) represent some of the most common neurodegenerative disorders whose steady increase in prevalence is having a [...] Read more.
Several neurodegenerative disorders are characterized by the accumulation of misfolded proteins and are collectively known as proteinopathies. Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD) represent some of the most common neurodegenerative disorders whose steady increase in prevalence is having a major socio-economic impact on our society. Multiple laboratories have reported hundreds of changes in gene expression in selective brain regions of AD, PD, and HD brains. While the mechanisms underlying these changes remain an active area of investigation, alterations in the expression of noncoding RNAs, which are common in AD, PD, and HD, may account for some of the changes in gene expression in proteinopathies. In this review, we discuss the role of miR-128, which is highly expressed in mammalian brains, in AD, PD, and HD. We highlight how alterations in miR-128 may account, at least in part, for the gene expression changes associated with proteinopathies. Indeed, miR-128 is involved, among other things, in the regulation of neuronal plasticity, cytoskeletal organization, and neuronal death, events linked to various proteinopathies. For example, reducing the expression of miR-128 in a mouse model of AD ameliorates cognitive deficits and reduces neuropathology. Overall, the data in the literature suggest that targeting miR-128 might be beneficial to mitigate the behavioral phenotype associated with these diseases. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Brain Aging and Alzheimer’s Disease)
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13 pages, 897 KiB  
Review
The Nerve Growth Factor Receptor (NGFR/p75NTR): A Major Player in Alzheimer’s Disease
by Francesco Bruno, Paolo Abondio, Alberto Montesanto, Donata Luiselli, Amalia C. Bruni and Raffaele Maletta
Int. J. Mol. Sci. 2023, 24(4), 3200; https://doi.org/10.3390/ijms24043200 - 6 Feb 2023
Cited by 7 | Viewed by 3307
Abstract
Alzheimer’s disease (AD) represents the most prevalent type of dementia in elderly people, primarily characterized by brain accumulation of beta-amyloid (Aβ) peptides, derived from Amyloid Precursor Protein (APP), in the extracellular space (amyloid plaques) and intracellular deposits of the hyperphosphorylated form [...] Read more.
Alzheimer’s disease (AD) represents the most prevalent type of dementia in elderly people, primarily characterized by brain accumulation of beta-amyloid (Aβ) peptides, derived from Amyloid Precursor Protein (APP), in the extracellular space (amyloid plaques) and intracellular deposits of the hyperphosphorylated form of the protein tau (p-tau; tangles or neurofibrillary aggregates). The Nerve growth factor receptor (NGFR/p75NTR) represents a low-affinity receptor for all known mammalians neurotrophins (i.e., proNGF, NGF, BDNF, NT-3 e NT-4/5) and it is involved in pathways that determine both survival and death of neurons. Interestingly, also Aβ peptides can blind to NGFR/p75NTR making it the “ideal” candidate in mediating Aβ-induced neuropathology. In addition to pathogenesis and neuropathology, several data indicated that NGFR/p75NTR could play a key role in AD also from a genetic perspective. Other studies suggested that NGFR/p75NTR could represent a good diagnostic tool, as well as a promising therapeutic target for AD. Here, we comprehensively summarize and review the current experimental evidence on this topic. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Brain Aging and Alzheimer’s Disease)
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13 pages, 592 KiB  
Review
Applications of CRISPR-Cas9 in Alzheimer’s Disease and Related Disorders
by Laura M. De Plano, Giovanna Calabrese, Sabrina Conoci, Salvatore P. P. Guglielmino, Salvatore Oddo and Antonella Caccamo
Int. J. Mol. Sci. 2022, 23(15), 8714; https://doi.org/10.3390/ijms23158714 - 5 Aug 2022
Cited by 15 | Viewed by 5530
Abstract
Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease represent some of the most prevalent neurodegenerative disorders afflicting millions of people worldwide. Unfortunately, there is a lack of efficacious treatments to cure or stop the progression of these disorders. While the causes [...] Read more.
Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease represent some of the most prevalent neurodegenerative disorders afflicting millions of people worldwide. Unfortunately, there is a lack of efficacious treatments to cure or stop the progression of these disorders. While the causes of such a lack of therapies can be attributed to various reasons, the disappointing results of recent clinical trials suggest the need for novel and innovative approaches. Since its discovery, there has been a growing excitement around the potential for CRISPR-Cas9 mediated gene editing to identify novel mechanistic insights into disease pathogenesis and to mediate accurate gene therapy. To this end, the literature is rich with experiments aimed at generating novel models of these disorders and offering proof-of-concept studies in preclinical animal models validating the great potential and versatility of this gene-editing system. In this review, we provide an overview of how the CRISPR-Cas9 systems have been used in these neurodegenerative disorders. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Brain Aging and Alzheimer’s Disease)
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