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Biomolecules
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Molecular Aspects of Cellular Dysfunction in Alzheimer's Disease
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Molecular Aspects of Cellular Dysfunction in Alzheimer's Disease

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (31 July 2021) | Viewed by 20793

Special Issue Editors

Dr. Sara Merlo

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Guest Editor
Department of Biomedical and Biotechnological Sciences (BIOMETEC), Section of Pharmacology,University of Catania, Via Santa Sofia 97, 95123 Catania, Italy
Interests: Alzheimer’s Disease; beta-amyloid toxicity; neurodegeneration; neuroinflammation; glial-neuron cross-talk, microglia, sirtuins; melatonin; estrogens
Dr. Dmitry Lim

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Guest Editor
Department of Pharmaceutical Science, University of Piemonte Orientale, 28100 Novara, Italy
Interests: calcium signaling; astrocytes; calcineurin; Alzheimer’s disease
Special Issues, Collections and Topics in MDPI journals
Dr. Simona Federica Spampinato

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Guest Editor
Department of Biomedical and Biotechnological Sciences (BIOMETEC), Section of PharmacologyUniversity of Catania, Via Santa Sofia 97, 95123 Catania, Italy
Interests: neurodegeneration; neuroinflammation; BBB, astrocytes; endothelial cells; glial cells; beta amyloid; estrogens; sphingosine 1-phosphate; metabotropic glutamate receptors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

Alzheimer’s disease (AD) is a worldwide emergency, destined to worsen as population mean age increases. The efforts in the last decade of research have led to an increased knowledge of how the disease starts and progresses, but disease-modifying therapies and preventive strategies are still lacking. It has become evident that AD develops extremely slowly over the years, and this has made it obvious that post-symptomatic intervention is hampered by the advanced neurodegeneration that does not allow nervous tissue to be efficiently restored. Importantly, it appears that molecular compensatory mechanisms exist that can lead to greater resilience to cognitive decline, but these still need to be more clearly defined. Moreover, recent advances in understanding the intricate and reciprocal molecular cross-talk between cell types in the central nervous system suggests that the detailed characterization of cell-specific molecular abnormalities may lead to a better understanding of complex phenomena underlying AD pathogenesis. This is particularly true for glia–neuron interaction, in which the homeostatic support of glial cells is of paramount importance, for blood–brain barrier impairment and inflammation, which are believed to be crucial in AD and a shared mechanism with other neurodegenerative conditions. In this view, understanding the molecular aspects of cellular dysfunction in AD, revealing the time course of molecular and cellular events that slowly lead to degeneration, and aiming to identify biomarkers and therapeutic targets all seem of extreme importance.

This Special Issue aims to collect all work focused on these modern challenges in molecular AD research. Both original and review article contributions will be welcome.

Dr. Sara Merlo
Assoc. Prof. Dmitry Lim
Dr. Simona Federica Spampinato
Guest Editors

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. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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
  • Neurodegeneration
  • Neuroinflammation
  • Glial–neuron crosstalk
  • Blood–brain barrier
  • Early molecular compensatory mechanisms
  • Neurons
  • Astrocytes
  • Oligodendrocytes
  • Microglia
  • Endothelial cells

Published Papers (6 papers)

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Editorial

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4 pages, 860 KiB  
Editorial
Molecular Aspects of Cellular Dysfunction in Alzheimer’s Disease: The Need for a Holistic View of the Early Pathogenesis
by Sara Merlo, Simona Federica Spampinato and Dmitry Lim
Biomolecules 2021, 11(12), 1807; https://doi.org/10.3390/biom11121807 - 01 Dec 2021
Cited by 4 | Viewed by 2042
Abstract
Alzheimer’s disease (AD) is the most common cause of dementia in the elderly, a socio-economic burden destined to worsen with increased population aging [...] Full article
(This article belongs to the Special Issue Molecular Aspects of Cellular Dysfunction in Alzheimer's Disease)
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Research

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18 pages, 2157 KiB  
Article
Sublingual AKBA Exerts Antidepressant Effects in the Aβ-Treated Mouse Model
by Maria Grazia Morgese, Maria Bove, Matteo Francavilla, Stefania Schiavone, Stefania Dimonte, Anna Laura Colia, Matteo Bevilacqua, Luigia Trabace and Paolo Tucci
Biomolecules 2021, 11(5), 686; https://doi.org/10.3390/biom11050686 - 03 May 2021
Cited by 14 | Viewed by 2486
Abstract
The 3-O-acetyl-11-keto-β-boswellic acid (AKBA) is the most active compound of Boswellia serrata proposed for treating neurodegenerative disorders, including Alzheimer’s disease (AD), characterized in its early phase by alteration in mood. Accordingly, we have previously demonstrated that an intracerebroventricular injection of soluble amyloid beta [...] Read more.
The 3-O-acetyl-11-keto-β-boswellic acid (AKBA) is the most active compound of Boswellia serrata proposed for treating neurodegenerative disorders, including Alzheimer’s disease (AD), characterized in its early phase by alteration in mood. Accordingly, we have previously demonstrated that an intracerebroventricular injection of soluble amyloid beta 1-42 (Aβ) peptide evokes a depressive-like phenotype in rats. We tested the protective effects of AKBA in the mouse model of an Aβ-induced depressive-like phenotype. We evaluated the depressive-like behavior by using the tail suspension test (TST) and the splash test (ST). Behavioral analyses were accompanied by neurochemical quantifications, such as glutamate (GLU), kynurenine (KYN) and monoamines, and by biochemical measurements, such as glial fibrillary acid protein (GFAP), CD11b and nuclear factor kappa B (NF-kB), in mice prefrontal cortex (PFC) and hippocampus (HIPP). AKBA prevented the depressive-like behaviors induced by Aβ administration, since we recorded a reduction in latency to initiate self-care and total time spent to perform self-care in the ST and reduced time of immobility in the TST. Likewise, the increase in GLU and KYN levels in PFC and HIPP induced by the peptide injection were reverted by AKBA administration, as well as the displayed increase in levels of GFAP and NF-kB in both PFC and HIPP, but not in CD11b. Therefore, AKBA might represent a food supplement suitable as an adjuvant for therapy of depression in early-stage AD. Full article
(This article belongs to the Special Issue Molecular Aspects of Cellular Dysfunction in Alzheimer's Disease)
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27 pages, 7749 KiB  
Article
Spreading of Beta-Amyloid in Organotypic Mouse Brain Slices and Microglial Elimination and Effects on Cholinergic Neurons
by Kurt Moelgg, Faryal Jummun and Christian Humpel
Biomolecules 2021, 11(3), 434; https://doi.org/10.3390/biom11030434 - 15 Mar 2021
Cited by 10 | Viewed by 2784
Abstract
The extracellular deposition of β-amyloid (Aβ) is one of the major characteristics in Alzheimer´s disease (AD). The “spreading hypothesis” suggests that a pathological protein (similar to prions) spreads over the entire brain. The aim of the present study was to use organotypic brain [...] Read more.
The extracellular deposition of β-amyloid (Aβ) is one of the major characteristics in Alzheimer´s disease (AD). The “spreading hypothesis” suggests that a pathological protein (similar to prions) spreads over the entire brain. The aim of the present study was to use organotypic brain slices of postnatal day 8–10 mice. Using collagen hydrogels, we applied different Aβ peptides onto brain slices and analyzed spreading as well as glial reactions after eight weeks of incubation. Our data showed that from all tested Aβ peptides, human Aβ42 had the most potent activity to spread over into adjacent “target” areas. This effect was potentiated when brain slices from transgenic AD mice (APP_SweDI) were cultured. When different brain areas were connected to the “target slice” the spreading activity was more intense, originating from ventral striatum and brain stem. Reactive glial-fibrillary acidic protein (GFAP) astrogliosis increased over time, but Aβ depositions co-localized only with Iba1+ microglia but not with astrocytes. Application of human Aβ42 did not cause a degeneration of cholinergic neurons. We concluded that human Aβ42 spreads over into other “target areas”, causing activation of glial cells. Most of the spread Aβ42 was taken up by microglia, and thus toxic free Aβ could not damage cholinergic neurons. Full article
(This article belongs to the Special Issue Molecular Aspects of Cellular Dysfunction in Alzheimer's Disease)
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Review

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17 pages, 704 KiB  
Review
Looking at Alzheimer’s Disease Pathogenesis from the Nuclear Side
by Laura D’Andrea, Ramona Stringhi, Monica Di Luca and Elena Marcello
Biomolecules 2021, 11(9), 1261; https://doi.org/10.3390/biom11091261 - 24 Aug 2021
Cited by 4 | Viewed by 3409
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder representing the most common form of dementia. It is biologically characterized by the deposition of extracellular amyloid-β (Aβ) senile plaques and intracellular neurofibrillary tangles, constituted by hyperphosphorylated tau protein. The key protein in AD pathogenesis is [...] Read more.
Alzheimer’s disease (AD) is a neurodegenerative disorder representing the most common form of dementia. It is biologically characterized by the deposition of extracellular amyloid-β (Aβ) senile plaques and intracellular neurofibrillary tangles, constituted by hyperphosphorylated tau protein. The key protein in AD pathogenesis is the amyloid precursor protein (APP), which is cleaved by secretases to produce several metabolites, including Aβ and APP intracellular domain (AICD). The greatest genetic risk factor associated with AD is represented by the Apolipoprotein E ε4 (APOE ε4) allele. Importantly, all of the above-mentioned molecules that are strictly related to AD pathogenesis have also been described as playing roles in the cell nucleus. Accordingly, evidence suggests that nuclear functions are compromised in AD. Furthermore, modulation of transcription maintains cellular homeostasis, and alterations in transcriptomic profiles have been found in neurodegenerative diseases. This report reviews recent advancements in the AD players-mediated gene expression. Aβ, tau, AICD, and APOE ε4 localize in the nucleus and regulate the transcription of several genes, part of which is involved in AD pathogenesis, thus suggesting that targeting nuclear functions might provide new therapeutic tools for the disease. Full article
(This article belongs to the Special Issue Molecular Aspects of Cellular Dysfunction in Alzheimer's Disease)
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21 pages, 2964 KiB  
Review
Retinal Dysfunction in Alzheimer’s Disease and Implications for Biomarkers
by Chunyan Liao, Jinying Xu, Yu Chen and Nancy Y. Ip
Biomolecules 2021, 11(8), 1215; https://doi.org/10.3390/biom11081215 - 16 Aug 2021
Cited by 16 | Viewed by 3574
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that manifests as cognitive deficits and memory decline, especially in old age. Several biomarkers have been developed to monitor AD progression. Given that the retina and brain share some similarities including features related to anatomical [...] Read more.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that manifests as cognitive deficits and memory decline, especially in old age. Several biomarkers have been developed to monitor AD progression. Given that the retina and brain share some similarities including features related to anatomical composition and neurological functions, the retina is closely associated with the progression of AD. Herein, we review the evidence of retinal dysfunction in AD, particularly at the early stage, together with the underlying molecular mechanisms. Furthermore, we compared the retinal pathologies of AD and other ophthalmological diseases and summarized potential retinal biomarkers measurable by existing technologies for detecting AD, providing insights for the future development of diagnostic tools. Full article
(This article belongs to the Special Issue Molecular Aspects of Cellular Dysfunction in Alzheimer's Disease)
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32 pages, 1382 KiB  
Review
Alternative Targets to Fight Alzheimer’s Disease: Focus on Astrocytes
by Marta Valenza, Roberta Facchinetti, Giorgia Menegoni, Luca Steardo and Caterina Scuderi
Biomolecules 2021, 11(4), 600; https://doi.org/10.3390/biom11040600 - 19 Apr 2021
Cited by 17 | Viewed by 5425
Abstract
The available treatments for patients affected by Alzheimer’s disease (AD) are not curative. Numerous clinical trials have failed during the past decades. Therefore, scientists need to explore new avenues to tackle this disease. In the present review, we briefly summarize the pathological mechanisms [...] Read more.
The available treatments for patients affected by Alzheimer’s disease (AD) are not curative. Numerous clinical trials have failed during the past decades. Therefore, scientists need to explore new avenues to tackle this disease. In the present review, we briefly summarize the pathological mechanisms of AD known so far, based on which different therapeutic tools have been designed. Then, we focus on a specific approach that is targeting astrocytes. Indeed, these non-neuronal brain cells respond to any insult, injury, or disease of the brain, including AD. The study of astrocytes is complicated by the fact that they exert a plethora of homeostatic functions, and their disease-induced changes could be context-, time-, and disease specific. However, this complex but fervent area of research has produced a large amount of data targeting different astrocytic functions using pharmacological approaches. Here, we review the most recent literature findings that have been published in the last five years to stimulate new hypotheses and ideas to work on, highlighting the peculiar ability of palmitoylethanolamide to modulate astrocytes according to their morpho-functional state, which ultimately suggests a possible potential disease-modifying therapeutic approach for AD. Full article
(This article belongs to the Special Issue Molecular Aspects of Cellular Dysfunction in Alzheimer's Disease)
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