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Brain Endothelial Dysfunction a Key Target in Neurodegenerative Diseases

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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 2022) | Viewed by 13217

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Special Issue Editors

Dr. Alberto Ouro

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Guest Editor

NeuroAging Group (NEURAL), Clinical Neurosciences Research Laboratories (LINCs), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
Interests: sphingolipids; inflammation; signaling pathways; neurosciences; Alzheimer’s disease; memory; cancer
Special Issues, Collections and Topics in MDPI journals

Dr. Daniel Romaus-Sanjurjo

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Guest Editor

NeuroAging Group (NEURAL), Clinical Neurosciences Research Laboratories (LINCs), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
Interests: spinal cord injury; neuroprotection; axonal growth; signaling pathways; neurosciences; Alzheimer’s disease; GABA receptors

Special Issue Information

Dear Colleagues,

It is well established that several risk factors, such as genetic, diet, aging, or previous cerebrovascular diseases, are associated with the possibility of developing neurodegenerative diseases, such as Alzheimer's or Parkinson's disease. However, since there is currently no target to stop or slow this neurodegeneration, it is tempting to hypothesize that other known or unknown factors are playing pivotal roles in the onset of these neurodegenerative conditions. Indeed, many cellular mechanisms underlying neurodegeneration start “quietly” a long time before clinical symptoms are detected. Although the exact cause of synaptic dysfunction and neurodegeneration in the early stages is largely unknown, in recent years, the involvement of brain endothelial dysfunction in the initial pathophysiological processes of neurodegenerative diseases has been defined. During neurodegeneration, cerebral arterioles suffer a progressive alteration leading to an increased permeability of the blood–brain barrier. This increases the rate in the passage of potential toxic and pro-inflammatory components to cerebral parenchyma, causing microglia activation and neurotoxicity.

However, the cellular mechanism underlying these cerebrovascular damages is not fully understood. Therefore, detection of early biomarkers that lead to the identification of cerebral endothelial dysfunction may constitute new diagnostic and therapeutic targets for neurodegenerative diseases at early stages.

In this Special Issue, we invite potential authors to contribute with original and/or review articles that provide a new perspective on this topic.

Dr. Alberto Ouro
Dr. Daniel Romaus-Sanjurjo
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. 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

neurodegeneration
cerebrovascular
endothelial dysfunction
risk factors
post-operative stroke
neuroprotection
biomarkers
synapses
microglia
neuronal death
inflammation
immune system

Published Papers (5 papers)

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Research

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14 pages, 687 KiB

Open AccessArticle

Bacterial DNAemia in Alzheimer’s Disease and Mild Cognitive Impairment: Association with Cognitive Decline, Plasma BDNF Levels, and Inflammatory Response

by Robertina Giacconi, Patrizia D’Aquila, Marta Balietti, Cinzia Giuli, Marco Malavolta, Francesco Piacenza, Laura Costarelli, Demetrio Postacchini, Giuseppe Passarino, Dina Bellizzi and Mauro Provinciali

Int. J. Mol. Sci. 2023, 24(1), 78; https://doi.org/10.3390/ijms24010078 - 21 Dec 2022

Cited by 4 | Viewed by 1632

Abstract

Microbial dysbiosis (MD) provokes gut barrier alterations and bacterial translocation in the bloodstream. The increased blood bacterial DNA (BB-DNA) may promote peripheral- and neuro-inflammation, contributing to cognitive impairment. MD also influences brain-derived neurotrophic factor (BDNF) production, whose alterations contribute to the etiopathogenesis of Alzheimer’s disease (AD). The purpose of this study is to measure BB-DNA in healthy elderly controls (EC), and in patients with mild cognitive impairment (MCI) and AD to explore the effect on plasma BDNF levels (pBDNF), the inflammatory response, and the association with cognitive decline during a two-year follow-up. Baseline BB-DNA and pBDNF were significantly higher in MCI and AD than in EC. BB-DNA was positively correlated with pBDNF in AD, plasma Tumor necrosis factor-alpha (TNF-α), and Interleukin-10 (IL-10) levels in MCI. AD patients with BB-DNA values above the 50th percentile had lower baseline Mini-Mental State Examination (MMSE). After a two-year follow-up, AD patients with the highest BB-DNA tertile had a worse cognitive decline, while higher BB-DNA levels were associated with higher TNF-α and lower IL-10 in MCI. Our study demonstrates that, in early AD, the higher the BB-DNA levels, the higher the pBDNF levels, suggesting a defensive attempt; BB-DNA seems to play a role in the AD severity/progression; in MCI, higher BB-DNA may trigger an increased inflammatory response. Full article

(This article belongs to the Special Issue Brain Endothelial Dysfunction a Key Target in Neurodegenerative Diseases)

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13 pages, 1400 KiB

Open AccessArticle

Central Stimulatory Effect of Kynurenic Acid on BDNF-TrkB Signaling and BER Enzymatic Activity in the Hippocampal CA1 Field in Sheep

by Katarzyna Roszkowicz-Ostrowska, Patrycja Młotkowska, Paweł Kowalczyk, Elżbieta Marciniak, Marcin Barszcz and Tomasz Misztal

Int. J. Mol. Sci. 2023, 24(1), 136; https://doi.org/10.3390/ijms24010136 - 21 Dec 2022

Cited by 1 | Viewed by 1260

Abstract

Deficiency of neurotrophic factors and oxidative DNA damage are common causes of many neurodegenerative diseases. Recently, the importance of kynurenic acid (KYNA), an active metabolite of tryptophan, has increased as a neuroprotective molecule in the brain. Therefore, the present study tested the hypothesis that centrally acting KYNA would positively affect: (1) brain-derived neurotrophic factor (BDNF)-tyrosine receptor kinase B (TrkB) signaling and (2) selected base excision repair (BER) pathway enzymes activities in the hippocampal CA1 field in sheep. Both lower (20 μg in total) and higher (100 μg in total) doses of KYNA infused into the third brain ventricle differentially increased the abundance of BDNF and TrkB mRNA in the CA1 field; additionally, the higher dose increased BDNF tissue concentration. The lower dose of KYNA increased mRNA expression for 8-oxoguanine glycosylase (OGG1), N-methylpurine DNA glycosylase (MPG), and thymine DNA glycosylase and stimulated the repair of 1,N6-ethenodeoxyadenosine and 3,N4-ethenodeoxy-cytosine as determined by the excision efficiency of lesioned nucleobases. The higher dose increased the abundance of OGG1 and MPG transcripts, however, its stimulatory effect on repair activity was less pronounced in all cases compared to the lower dose. The increased level of AP-endonuclease mRNA expression was dose-dependent. In conclusion, the potential neurotrophic and neuroprotective effects of KYNA in brain cells may involve stimulation of the BDNF-TrkB and BER pathways. Full article

(This article belongs to the Special Issue Brain Endothelial Dysfunction a Key Target in Neurodegenerative Diseases)

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17 pages, 10158 KiB

Open AccessArticle

A Novel Rodent Model of Hypertensive Cerebral Small Vessel Disease with White Matter Hyperintensities and Peripheral Oxidative Stress

by Reut Guy, Rotem Volkman, Ella Wilczynski, Chana Yagil, Yoram Yagil, Michael Findler, Eitan Auriel, Uri Nevo and Daniel Offen

Int. J. Mol. Sci. 2022, 23(11), 5915; https://doi.org/10.3390/ijms23115915 - 25 May 2022

Cited by 6 | Viewed by 2572

Abstract

Cerebral small vessel disease (CSVD) is the second most common cause of stroke and a major contributor to dementia. Manifestations of CSVD include cerebral microbleeds, intracerebral hemorrhages (ICH), lacunar infarcts, white matter hyperintensities (WMH) and enlarged perivascular spaces. Chronic hypertensive models have been found to reproduce most key features of the disease. Nevertheless, no animal models have been identified to reflect all different aspects of the human disease. Here, we described a novel model for CSVD using salt-sensitive ‘Sabra’ hypertension-prone rats (SBH/y), which display chronic hypertension and enhanced peripheral oxidative stress. SBH/y rats were either administered deoxycorticosteroid acetate (DOCA) (referred to as SBH/y-DOCA rats) or sham-operated and provided with 1% NaCl in drinking water. Rats underwent neurological assessment and behavioral testing, followed by ex vivo MRI and biochemical and histological analyses. SBH/y-DOCA rats show a neurological decline and cognitive impairment and present multiple cerebrovascular pathologies associated with CSVD, such as ICH, lacunes, enlarged perivascular spaces, blood vessel stenosis, BBB permeability and inflammation. Remarkably, SBH/y-DOCA rats show severe white matter pathology as well as WMH, which are rarely reported in commonly used models. Our model may serve as a novel platform for further understanding the mechanisms underlying CSVD and for testing novel therapeutics. Full article

(This article belongs to the Special Issue Brain Endothelial Dysfunction a Key Target in Neurodegenerative Diseases)

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Review

Jump to: Research

27 pages, 1833 KiB

Open AccessReview

Endothelial Dysfunction in Neurodegenerative Diseases

by Yao-Ching Fang, Yi-Chen Hsieh, Chaur-Jong Hu and Yong-Kwang Tu

Int. J. Mol. Sci. 2023, 24(3), 2909; https://doi.org/10.3390/ijms24032909 - 2 Feb 2023

Cited by 20 | Viewed by 3148

Abstract

The cerebral vascular system stringently regulates cerebral blood flow (CBF). The components of the blood–brain barrier (BBB) protect the brain from pathogenic infections and harmful substances, efflux waste, and exchange substances; however, diseases develop in cases of blood vessel injuries and BBB dysregulation. Vascular pathology is concurrent with the mechanisms underlying aging, Alzheimer’s disease (AD), and vascular dementia (VaD), which suggests its involvement in these mechanisms. Therefore, in the present study, we reviewed the role of vascular dysfunction in aging and neurodegenerative diseases, particularly AD and VaD. During the development of the aforementioned diseases, changes occur in the cerebral blood vessel morphology and local cells, which, in turn, alter CBF, fluid dynamics, and vascular integrity. Chronic vascular inflammation and blood vessel dysregulation further exacerbate vascular dysfunction. Multitudinous pathogenic processes affect the cerebrovascular system, whose dysfunction causes cognitive impairment. Knowledge regarding the pathophysiology of vascular dysfunction in neurodegenerative diseases and the underlying molecular mechanisms may lead to the discovery of clinically relevant vascular biomarkers, which may facilitate vascular imaging for disease prevention and treatment. Full article

(This article belongs to the Special Issue Brain Endothelial Dysfunction a Key Target in Neurodegenerative Diseases)

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30 pages, 2221 KiB

Open AccessReview

Contribution of Extracellular Vesicles and Molecular Chaperones in Age-Related Neurodegenerative Disorders of the CNS

by Leila Noori, Kamila Filip, Zohreh Nazmara, Simin Mahakizadeh, Gholamreza Hassanzadeh, Celeste Caruso Bavisotto, Fabio Bucchieri, Antonella Marino Gammazza, Francesco Cappello, Maciej Wnuk and Federica Scalia

Int. J. Mol. Sci. 2023, 24(2), 927; https://doi.org/10.3390/ijms24020927 - 4 Jan 2023

Cited by 5 | Viewed by 3842

Abstract

Many neurodegenerative disorders are characterized by the abnormal aggregation of misfolded proteins that form amyloid deposits which possess prion-like behavior such as self-replication, intercellular transmission, and consequent induction of native forms of the same protein in surrounding cells. The distribution of the accumulated proteins and their correlated toxicity seem to be involved in the progression of nervous system degeneration. Molecular chaperones are known to maintain proteostasis, contribute to protein refolding to protect their function, and eliminate fatally misfolded proteins, prohibiting harmful effects. However, chaperone network efficiency declines during aging, prompting the onset and the development of neurological disorders. Extracellular vesicles (EVs) are tiny membranous structures produced by a wide range of cells under physiological and pathological conditions, suggesting their significant role in fundamental processes particularly in cellular communication. They modulate the behavior of nearby and distant cells through their biological cargo. In the pathological context, EVs transport disease-causing entities, including prions, α-syn, and tau, helping to spread damage to non-affected areas and accelerating the progression of neurodegeneration. However, EVs are considered effective for delivering therapeutic factors to the nervous system, since they are capable of crossing the blood–brain barrier (BBB) and are involved in the transportation of a variety of cellular entities. Here, we review the neurodegeneration process caused mainly by the inefficiency of chaperone systems as well as EV performance in neuropathies, their potential as diagnostic biomarkers and a promising EV-based therapeutic approach. Full article

(This article belongs to the Special Issue Brain Endothelial Dysfunction a Key Target in Neurodegenerative Diseases)

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