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Unraveling the Molecular Pathways of Alzheimer's Disease

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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 (20 July 2022) | Viewed by 14502

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Special Issue Editor

Dr. Maite Mendioroz

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Guest Editor

Neuroepigenetics Laboratory-Navarrabiomed, Neurology Department-Complejo Hospitalario de Navarra, IdiSNA (Navarra Institute for Health Research), Pamplona, 31008 Navarra, Spain
Interests: microglia; adult neurogenesis; tau; amyloid; innate immunity; Neuroepigenetics; DNA methylation

Special Issue Information

Dear Colleagues,

Early diagnosis of Alzheimer's disease (AD) and the discovery of therapies to halt or significantly slow the course of the disease are daunting challenges facing our society. A deeper understanding of the molecular basis underlying the anatomopathological and clinical changes characteristic of AD would allow us to change the paradigm and identify promising therapeutic targets for these patients.

Examples of molecular pathways currently under active investigation would be age-related defects in autophagy capacity or oxidative stress conditioned by external stimuli, such as pollution or diet. Additional hypotheses would include changes in inflammatory molecules related to innate or adaptive immunity and a number of alterations in the molecular processes that influence adult neurogenesis. All the above must be considered without forgetting the molecular machinery that epigenetic mechanisms use to combine environment and genetic susceptibility in developing AD. All these processes and others have a molecular translation that needs to be elucidated in order to better understand the disease and seek therapeutic alternatives for AD.

Dr. Maite Mendioroz
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

molecular pathways
epigenetics
autophagy
microglia
adult neurogenesis
pollution
innate immunity
tau
amyloid

Published Papers (4 papers)

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Research

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20 pages, 3976 KiB

Open AccessArticle

The Rat Brain Transcriptome: From Infancy to Aging and Sporadic Alzheimer’s Disease-like Pathology

by Natalia A. Stefanova and Nataliya G. Kolosova

Int. J. Mol. Sci. 2023, 24(2), 1462; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24021462 - 11 Jan 2023

Cited by 5 | Viewed by 1818

Abstract

It has been suggested that functional traits of the adult brain—all of which are established early in life—may affect the brain’s susceptibility to Alzheimer’s disease (AD). Results of our previous studies on senescence-accelerated OXYS rats, a model of sporadic AD, support this hypothesis. Here, to elucidate the molecular genetic nature of the aberrations revealed during brain maturation, we analyzed transcriptomes (RNA-seq data) of the prefrontal cortex (PFC) and hippocampus of OXYS rats and Wistar (control) rats in the period of brain maturation critical for OXYS rats (ages P3 and P10; P: postnatal day). We found more than 1000 differentially expressed genes in both brain structures; functional analysis indicated reduced efficiency of the formation of neuronal contacts, presumably explained mainly by deficits of mitochondrial functions. Next, we compared differentially expressed genes in the rat PFC and hippocampus from infancy to the progressive stage of AD-like pathology (five ages in total). Three genes (Thoc3, Exosc8, and Smpd4) showed overexpression in both brain regions of OXYS rats throughout the lifespan. Thus, reduced efficiency of the formation of neural networks in the brain of OXYS rats in infancy likely contributes to the development of their AD-like pathology. Full article

(This article belongs to the Special Issue Unraveling the Molecular Pathways of Alzheimer's Disease)

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22 pages, 5426 KiB

Open AccessArticle

Neuroprotective Action of Coumarin Derivatives through Activation of TRKB-CREB-BDNF Pathway and Reduction of Caspase Activity in Neuronal Cells Expressing Pro-Aggregated Tau Protein

by Te-Hsien Lin, Kuo-Hsuan Chang, Ya-Jen Chiu, Zheng-Kui Weng, Ying-Chieh Sun, Wenwei Lin, Guey-Jen Lee-Chen and Chiung-Mei Chen

Int. J. Mol. Sci. 2022, 23(21), 12734; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232112734 - 22 Oct 2022

Cited by 9 | Viewed by 1862

Abstract

Hyperphosphorylation and aggregation of the microtubule binding protein tau is a neuropathological hallmark of Alzheimer’s disease/tauopathies. Tau neurotoxicity provokes alterations in brain-derived neurotrophic factor (BDNF)/tropomycin receptor kinase B (TRKB)/cAMP-response-element binding protein (CREB) signaling to contribute to neurodegeneration. Compounds activating TRKB may therefore provide beneficial effects in tauopathies. LM-031, a coumarin derivative, has demonstrated the potential to improve BDNF signaling in neuronal cells expressing pro-aggregated ΔK280 tau mutant. In this study, we investigated if LM-031 analogous compounds provide neuroprotection effects through interaction with TRKB in SH-SY5Y cells expressing ΔK280 tau_RD-DsRed folding reporter. All four LMDS compounds reduced tau aggregation and reactive oxygen species. Among them, LMDS-1 and -2 reduced caspase-1, caspase-6 and caspase-3 activities and promoted neurite outgrowth, and the effect was significantly reversed by knockdown of TRKB. Treatment of ERK inhibitor U0126 or PI3K inhibitor wortmannin decreased p-CREB, BDNF and BCL2 in these cells, implying that the neuroprotective effects of LMDS-1/2 are via activating TRKB downstream ERK, PI3K-AKT and CREB signaling. Furthermore, LMDS-1/2 demonstrated their ability to quench the intrinsic fluorescence of tryptophan residues within the extracellular domain of TRKB, thereby consolidating their interaction with TRKB. Our results suggest that LMDS-1/2 exert neuroprotection through activating TRKB signaling, and shed light on their potential application in therapeutics of Alzheimer’s disease/tauopathies. Full article

(This article belongs to the Special Issue Unraveling the Molecular Pathways of Alzheimer's Disease)

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Review

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16 pages, 17018 KiB

Open AccessReview

Therapeutic Potential of Allicin and Aged Garlic Extract in Alzheimer’s Disease

by Paola Tedeschi, Manuela Nigro, Alessia Travagli, Martina Catani, Alberto Cavazzini, Stefania Merighi and Stefania Gessi

Int. J. Mol. Sci. 2022, 23(13), 6950; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23136950 - 22 Jun 2022

Cited by 22 | Viewed by 4407

Abstract

Garlic, Allium sativum, has long been utilized for a number of medicinal purposes around the world, and its medical benefits have been well documented. The health benefits of garlic likely arise from a wide variety of components, possibly working synergistically. Garlic and garlic extracts, especially aged garlic extracts (AGEs), are rich in bioactive compounds, with potent anti-inflammatory, antioxidant and neuroprotective activities. In light of these effects, garlic and its components have been examined in experimental models of Alzheimer’s disease (AD), the most common form of dementia without therapy, and a growing health concern in aging societies. With the aim of offering an updated overview, this paper reviews the chemical composition, metabolism and bioavailability of garlic bioactive compounds. In addition, it provides an overview of signaling mechanisms triggered by garlic derivatives, with a focus on allicin and AGE, to improve learning and memory. Full article

(This article belongs to the Special Issue Unraveling the Molecular Pathways of Alzheimer's Disease)

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28 pages, 1138 KiB

Open AccessReview

Brain Metabolic Alterations in Alzheimer’s Disease

by Carlos G. Ardanaz, María J. Ramírez and Maite Solas

Int. J. Mol. Sci. 2022, 23(7), 3785; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073785 - 29 Mar 2022

Cited by 26 | Viewed by 5639

Abstract

The brain is one of the most energy-consuming organs in the body. Satisfying such energy demand requires compartmentalized, cell-specific metabolic processes, known to be complementary and intimately coupled. Thus, the brain relies on thoroughly orchestrated energy-obtaining agents, processes and molecular features, such as the neurovascular unit, the astrocyte–neuron metabolic coupling, and the cellular distribution of energy substrate transporters. Importantly, early features of the aging process are determined by the progressive perturbation of certain processes responsible for adequate brain energy supply, resulting in brain hypometabolism. These age-related brain energy alterations are further worsened during the prodromal stages of neurodegenerative diseases, namely Alzheimer’s disease (AD), preceding the onset of clinical symptoms, and are anatomically and functionally associated with the loss of cognitive abilities. Here, we focus on concrete neuroenergetic features such as the brain’s fueling by glucose and lactate, the transporters and vascular system guaranteeing its supply, and the metabolic interactions between astrocytes and neurons, and on its neurodegenerative-related disruption. We sought to review the principles underlying the metabolic dimension of healthy and AD brains, and suggest that the integration of these concepts in the preventive, diagnostic and treatment strategies for AD is key to improving the precision of these interventions. Full article

(This article belongs to the Special Issue Unraveling the Molecular Pathways of Alzheimer's Disease)

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