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Alterations of Cell-to-Cell Communication in the Aging Brain and in Neurological 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 (15 November 2022) | Viewed by 12360

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Dr. Francesc Xavier Guix

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Centre for Molecular Biology Severo Ochoa, Spanish National Research Council (CSIC), Madrid, Spain
Interests: aging; neurodegenerative diseases; extracellular vesicles

Special Issue Information

Dear Colleagues,

Increasing evidence suggests that alterations to the interaction between the different cell types that integrate the central nervous system (CNS) play an important role in aging and in many neurological conditions.

Intercellular communication is essential to regulate many physiological aspects of the CNS. Vascular endothelial cells and pericytes interact with neurons and glial cells to form a functional neurovascular unit responsible for locally regulating the cerebral blood flow according to neuronal activity in specific areas of the brain. Compromised blood–brain barrier (BBB) integrity in aging but also in brain diseases such as infectious/inflammatory diseases, epilepsy, ischemic stroke and neurodegenerative diseases leads to neuronal injury and glial cell death. In turn, astrocytes and microglia play a dual role by disrupting or protecting the BBB, depending on the context. On the other side, during aging, but also in some neurodegenerative disorders (i.e., Alzheimer’s disease), neurons, astrocytes and microglia can acquire a senescence-associated secretory phenotype (SASP), a senescent state that is characterized by the secretion of inflammatory cytokines, growth factors, proteases or extracellular vesicles (EVs). SASP affects neighboring non-senescent cells in many ways, including the reduction of DNA repair. In recent years, a special focus was given to the role played by EVs in the cell-to-cell transmission of toxic proteins in neurodegenerative disorders and in the development of brain cancer.

The overarching aim of this Special Issue is to highlight the role of intercellular communication in the dysfunction of the brain occurring during aging and in neurological conditions. Authors are encouraged to submit original research and reviews on the alteration of the CNS intercellular communication in: i) aging, ii) neurodegenerative diseases and psychiatric disorders, iii) cerebrovascular conditions and iv) brain cancer.

Dr. Francesc Xavier Guix
Guest Editor

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Keywords

intercellular communication
brain cancer
blood–brain barrier (BBB)
aging
neurodegenerative disorders

Published Papers (5 papers)

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Research

16 pages, 5593 KiB

Open AccessArticle

Amyloid β-Peptide Causes the Permanent Activation of CaMKIIα through Its Oxidation

by Pol Picón-Pagès, Hugo Fanlo-Ucar, Víctor Herrera-Fernández, Sira Ausellé-Bosch, Lorena Galera-López, Daniela A. Gutiérrez, Andrés Ozaita, Alejandra R. Álvarez, Baldomero Oliva and Francisco J. Muñoz

Int. J. Mol. Sci. 2022, 23(23), 15169; https://doi.org/10.3390/ijms232315169 - 2 Dec 2022

Cited by 1 | Viewed by 1901

Abstract

Alzheimer’s disease (AD) is characterised by the presence of extracellular amyloid plaques in the brain. They are composed of aggregated amyloid beta-peptide (Aβ) misfolded into beta-sheets which are the cause of the AD memory impairment and dementia. Memory depends on the hippocampal formation and maintenance of synapses by long-term potentiation (LTP), whose main steps are the activation of NMDA receptors, the phosphorylation of CaMKIIα and the nuclear translocation of the transcription factor CREB. It is known that Aβ oligomers (oAβ) induce synaptic loss and impair the formation of new synapses. Here, we have studied the effects of oAβ on CaMKIIα. We found that oAβ produce reactive oxygen species (ROS), that induce CaMKIIα oxidation in human neuroblastoma cells as we assayed by western blot and immunofluorescence. Moreover, this oxidized isoform is significantly present in brain samples from AD patients. We found that the oxidized CaMKIIα is active independently of the binding to calcium/calmodulin, and that CaMKIIα phosphorylation is mutually exclusive with CaMKIIα oxidation as revealed by immunoprecipitation and western blot. An in silico modelling of the enzyme was also performed to demonstrate that oxidation induces an activated state of CaMKIIα. In brains from AD transgenic models of mice and in primary cultures of murine hippocampal neurons, we demonstrated that the oxidation of CaMKIIα induces the phosphorylation of CREB and its translocation to the nucleus to promote the transcription of ARC and BDNF. Our data suggests that CaMKIIα oxidation would be a pro-survival mechanism that is triggered when a noxious stimulus challenges neurons as do oAβ. Full article

(This article belongs to the Special Issue Alterations of Cell-to-Cell Communication in the Aging Brain and in Neurological Diseases)

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18 pages, 17457 KiB

Open AccessArticle

Brain Regional Identity and Cell Type Specificity Landscape of Human Cortical Organoid Models

by Manuela Magni, Beatrice Bossi, Paola Conforti, Maura Galimberti, Fabio Dezi, Tiziana Lischetti, Xiaoling He, Roger A. Barker, Chiara Zuccato, Ira Espuny-Camacho and Elena Cattaneo

Int. J. Mol. Sci. 2022, 23(21), 13159; https://doi.org/10.3390/ijms232113159 - 29 Oct 2022

Cited by 3 | Viewed by 2245

Abstract

In vitro models of corticogenesis from pluripotent stem cells (PSCs) have greatly improved our understanding of human brain development and disease. Among these, 3D cortical organoid systems are able to recapitulate some aspects of in vivo cytoarchitecture of the developing cortex. Here, we tested three cortical organoid protocols for brain regional identity, cell type specificity and neuronal maturation. Overall, all protocols gave rise to organoids that displayed a time-dependent expression of neuronal maturation genes such as those involved in the establishment of synapses and neuronal function. Comparatively, guided differentiation methods without WNT activation generated the highest degree of cortical regional identity, whereas default conditions produced the broadest range of cell types such as neurons, astrocytes and hematopoietic-lineage-derived microglia cells. These results suggest that cortical organoid models produce diverse outcomes of brain regional identity and cell type specificity and emphasize the importance of selecting the correct model for the right application. Full article

(This article belongs to the Special Issue Alterations of Cell-to-Cell Communication in the Aging Brain and in Neurological Diseases)

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21 pages, 3103 KiB

Open AccessArticle

Examination of Intracellular GPCR-Mediated Signaling with High Temporal Resolution

by Nadine Gruteser and Arnd Baumann

Int. J. Mol. Sci. 2022, 23(15), 8516; https://doi.org/10.3390/ijms23158516 - 31 Jul 2022

Cited by 1 | Viewed by 1971

Abstract

The GTP-binding protein-coupled receptors (GPCRs) play important roles in physiology and neuronal signaling. More than a thousand genes, excluding the olfactory receptors, have been identified that encode these integral membrane proteins. Their pharmacological and functional properties make them fascinating targets for drug development, since various disease states can be treated and overcome by pharmacologically addressing these receptors and/or their downstream interacting partners. The activation of the GPCRs typically causes transient changes in the intracellular second messenger concentrations as well as in membrane conductance. In contrast to ion channel-mediated electrical signaling which results in spontaneous cellular responses, the GPCR-mediated metabotropic signals operate at a different time scale. Here we have studied the kinetics of two common GPCR-induced signaling pathways: (a) Ca²⁺ release from intracellular stores and (b) cyclic adenosine monophosphate (cAMP) production. The latter was monitored via the activation of cyclic nucleotide-gated (CNG) ion channels causing Ca²⁺ influx into the cell. Genetically modified and stably transfected cell lines were established and used in stopped-flow experiments to uncover the individual steps of the reaction cascades. Using two homologous biogenic amine receptors, either coupling to G_o/q or G_s proteins, allowed us to determine the time between receptor activation and signal output. With ~350 ms, the release of Ca²⁺ from intracellular stores was much faster than cAMP-mediated Ca²⁺ entry through CNG channels (~6 s). The measurements with caged compounds suggest that this difference is due to turnover numbers of the GPCR downstream effectors rather than the different reaction cascades, per se. Full article

(This article belongs to the Special Issue Alterations of Cell-to-Cell Communication in the Aging Brain and in Neurological Diseases)

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20 pages, 5676 KiB

Open AccessArticle

A Novel In Vivo Model for Multiplexed Analysis of Callosal Connections upon Cortical Damage

by Ana González-Manteiga, Carmen Navarro-González, Valentina Evita Sebestyén, Jose Manuel Saborit-Torres, Daniela Talhada, María de la Iglesia Vayá, Karsten Ruscher and Pietro Fazzari

Int. J. Mol. Sci. 2022, 23(15), 8224; https://doi.org/10.3390/ijms23158224 - 26 Jul 2022

Viewed by 1976

Abstract

Brain damage is the major cause of permanent disability and it is particularly relevant in the elderly. While most studies focused on the immediate phase of neuronal loss upon injury, much less is known about the process of axonal regeneration after damage. The development of new refined preclinical models to investigate neuronal regeneration and the recovery of brain tissue upon injury is a major unmet challenge. Here, we present a novel experimental paradigm in mice that entails the (i) tracing of cortico-callosal connections, (ii) a mechanical lesion of the motor cortex, (iii) the stereological and histological analysis of the damaged tissue, and (iv) the functional characterization of motor deficits. By combining conventional microscopy with semi-automated 3D reconstruction, this approach allows the analysis of fine subcellular structures, such as axonal terminals, with the tridimensional overview of the connectivity and tissue integrity around the lesioned area. Since this 3D reconstruction is performed in serial sections, multiple labeling can be performed by combining diverse histological markers. We provide an example of how this methodology can be used to study cellular interactions. Namely, we show the correlation between active microglial cells and the perineuronal nets that envelop parvalbumin interneurons. In conclusion, this novel experimental paradigm will contribute to a better understanding of the molecular and cellular interactions underpinning the process of cortical regeneration upon brain damage. Full article

(This article belongs to the Special Issue Alterations of Cell-to-Cell Communication in the Aging Brain and in Neurological Diseases)

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16 pages, 22151 KiB

Open AccessArticle

Extracellular Vesicles Derived from Young Neural Cultures Attenuate Astrocytic Reactivity In Vitro

by Daniel Almansa, Héctor Peinado, Raquel García-Rodríguez, Álvaro Casadomé-Perales, Carlos G. Dotti and Francesc X. Guix

Int. J. Mol. Sci. 2022, 23(3), 1371; https://doi.org/10.3390/ijms23031371 - 25 Jan 2022

Cited by 2 | Viewed by 3642

Abstract

Extracellular vesicles (EVs) play an important role in intercellular communication and are involved in both physiological and pathological processes. In the central nervous system (CNS), EVs secreted from different brain cell types exert a sundry of functions, from modulation of astrocytic proliferation and microglial activation to neuronal protection and regeneration. However, the effect of aging on the biological functions of neural EVs is poorly understood. In this work, we studied the biological effects of small EVs (sEVs) isolated from neural cells maintained for 14 or 21 days in vitro (DIV). We found that EVs isolated from 14 DIV cultures reduced the extracellular levels of lactate dehydrogenase (LDH), the expression levels of the astrocytic protein GFAP, and the complexity of astrocyte architecture suggesting a role in lowering the reactivity of astrocytes, while EVs produced by 21 DIV cells did not show any of the above effects. These results in an in vitro model pave the way to evaluate whether similar results occur in vivo and through what mechanisms. Full article

(This article belongs to the Special Issue Alterations of Cell-to-Cell Communication in the Aging Brain and in Neurological Diseases)

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Alterations of Cell-to-Cell Communication in the Aging Brain and in Neurological Diseases

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