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Biomedicines
Special Issues
Brain Injury and Neurodegeneration: Molecular, Functional, and Translational Approach 3.0
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Brain Injury and Neurodegeneration: Molecular, Functional, and Translational Approach 3.0

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: 31 March 2025 | Viewed by 7817

Special Issue Editors

Dr. Kumar Vaibhav

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Guest Editor
Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
Interests: traumatic brain injury; stroke; hemorrhages; Alzheimer’s disease; Parkinson’s disease; neuroinflammation; macrophages; neutrophils; T-cells; metabolism; cannabinoids; cannabinoid receptors; ischemic conditioning; edema; apoptosis; scavenging receptors; innate immune cells; innate lymphoid cells; cycloxygenase; mitochondria; RBCs; miRNA
Special Issues, Collections and Topics in MDPI journals
Dr. Meenakshi Ahluwalia

E-Mail Website
Guest Editor
Department of Pathology, Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
Interests: pathology; traumatic brain injury; macrophages; T-cells; cannabinoids; oxidative stress; pesticides; genetic alterations; genome sequencing; nucleic acid; imaging
Special Issues, Collections and Topics in MDPI journals
Dr. Pankaj Gaur

E-Mail Website
Guest Editor
Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA
Interests: brain functions; traumatic brain injury; stroke; hemorrhages; alzheimer’s disease; Parkinson’s disease; Neuroinflammation
Special Issues, Collections and Topics in MDPI journals
Dr. Pankaj Ahluwalia

E-Mail Website
Guest Editor
Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
Interests: pathology; COVID-19, neutrophils; lymphoid cells; genome sequencing; nucleic acid; testing; cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

With the advance of neuroscience research, we have come across different kinds of brain pathologies such as traumatic brain injury (TBI), hypoxic/hypobaric insults, hemorrhages, stroke, and neurological disorders such as Parkinson’s and Alzheimer’s diseases. Any insult to brain (mild or acute) is multifactorial and initiates a cascade of inflammation, necrotic, and apoptotic pathways. It has long been known that insult or injury to brain may lead to neurological disorders such as Alzheimer’s and Parkinson’s disease as time elapses, and genetic or environmental factors play important roles in the progression of disease. A large body of evidence has shown that oxidative stress, mitochondrial dysfunctions, protein aggregation and phosphorylation, excessive iron accumulation in the brain, and neuro-inflammation play a pivotal role in neurodegeneration and brain injuries. The absence of a specific cure to limit injury progression after insult has spurred the scientific community to study the mechanism behind the degenerative cascade and to explore different therapeutic strategies.

This Special Issue will provide a multidisciplinary platform for discussing the pathology and intervention of brain disorders. This Special Issue will emphasize the psychological, behavioral, inflammatory, and molecular mechanisms in the development of new preventive and therapeutic strategies to limit brain injury and neurodegenerative disorders. This Special Issue accepts original high-quality research articles that are not yet published or sought for publication. Please feel free to discuss with the editor.

Potential topics include but are not limited to the following:

  • Molecular and histological alterations in an injured brain;
  • Behavioral changes in an injured brain;
  • Hypoxic brain injury and the role of vasculature;
  • Traumatic brain injury: mechanism and prevention;
  • Brain injury: emotional and psychological stress;
  • Parkinson’s and Alzheimer’s disease;
  • Neurodegeneration: does it link to previous brain injury?
  • COVID-19: are brain pathologies involved?
  • Brain insult and cognitive impairment;
  • Intracerebral hemorrhages and hypoxia;
  • Stroke-induced molecular and functional alterations;
  • Prevention of brain insult by natural molecules and pharmaceuticals;
  • Bioanalytical studies and receptor-mediated mechanism of natural compounds for the prevention of different kind of brain injuries;
  • Mechanisms of action of pharmaceuticals and natural products targeting oxidative stress and neuroinflammation in injured brain;
  • Computational and genetic studies of brain injuries;
  • Brain injury: protein misfolding and mitochondrial dysfunction.

Dr. Kumar Vaibhav
Dr. Meenakshi Ahluwalia
Dr. Pankaj Gaur
Dr. Pankaj Ahluwalia
Guest Editors

Manuscript Submission Information

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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. Biomedicines 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 2600 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

  • brain injury
  • psychological stress
  • Parkinson’s disease
  • Alzheimer’s disease
  • stroke
  • neurodegeneration
  • hemorrhages
  • hypoxia
  • neuroinflammation
  • translational approaches
  • oxidative stress
  • COVID-19
  • gut–brain axis

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  • Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
  • Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
  • External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
  • e-Book format: Special Issues with more than 10 articles can be published as dedicated e-books, ensuring wide and rapid dissemination.

Further information on MDPI's Special Issue policies can be found here.

Published Papers (4 papers)

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Research

21 pages, 2095 KiB  
Article
Brain Volumetric Analysis Using Artificial Intelligence Software in Premanifest Huntington’s Disease Individuals from a Colombian Caribbean Population
by Margarita R. Ríos-Anillo, Mostapha Ahmad, Johan E. Acosta-López, Martha L. Cervantes-Henríquez, Maria C. Henao-Castaño, Maria T. Morales-Moreno, Fabián Espitia-Almeida, José Vargas-Manotas, Cristian Sánchez-Barros, David A. Pineda and Manuel Sánchez-Rojas
Biomedicines 2024, 12(10), 2166; https://doi.org/10.3390/biomedicines12102166 - 24 Sep 2024
Viewed by 1335
Abstract
Background and objectives: The premanifest phase of Huntington’s disease (HD) is characterized by the absence of motor symptoms and exhibits structural changes in imaging that precede clinical manifestation. This study aimed to analyze volumetric changes identified through brain magnetic resonance imaging (MRI) processed [...] Read more.
Background and objectives: The premanifest phase of Huntington’s disease (HD) is characterized by the absence of motor symptoms and exhibits structural changes in imaging that precede clinical manifestation. This study aimed to analyze volumetric changes identified through brain magnetic resonance imaging (MRI) processed using artificial intelligence (AI) software in premanifest HD individuals, focusing on the relationship between CAG triplet expansion and structural biomarkers. Methods: The study included 36 individuals descending from families affected by HD in the Department of Atlántico. Sociodemographic data were collected, followed by peripheral blood sampling to extract genomic DNA for quantifying CAG trinucleotide repeats in the Huntingtin gene. Brain volumes were evaluated using AI software (Entelai/IMEXHS, v4.3.4) based on MRI volumetric images. Correlations between brain volumes and variables such as age, sex, and disease status were determined. All analyses were conducted using SPSS (v. IBM SPSS Statistics 26), with significance set at p < 0.05. Results: The analysis of brain volumes according to CAG repeat expansion shows that individuals with ≥40 repeats evidence significant increases in cerebrospinal fluid (CSF) volume and subcortical structures such as the amygdalae and left caudate nucleus, along with marked reductions in cerebral white matter, the cerebellum, brainstem, and left pallidum. In contrast, those with <40 repeats show minimal or moderate volumetric changes, primarily in white matter and CSF. Conclusions: These findings suggest that CAG expansion selectively impacts key brain regions, potentially influencing the progression of Huntington’s disease, and that AI in neuroimaging could identify structural biomarkers long before clinical symptoms appear. Full article
(This article belongs to the Special Issue Brain Injury and Neurodegeneration: Molecular, Functional, and Translational Approach 3.0)
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Figure 1

Figure 1
<p>Comparison of global brain volumes according to CAG expansion. This figure compares the global brain volumes in three groups of individuals with different CAG triplet expansions: ≤26 (normal), 27 – 35 (intermediate), and &gt;40 (full penetrance). The structures evaluated include the brain parenchyma volume (<b>A</b>), cerebrospinal fluid (CSF) volume (<b>B</b>), gray matter volume (<b>C</b>), white matter volume (<b>D</b>). The <span class="html-italic">p</span> values indicate the statistical significance of the observed differences: (*** <span class="html-italic">p</span> &lt; 0.00001).</p> Full article ">Figure 2
<p>Subcortical structure volumes according to CAG triplet expansion. This figure compares the volumes of various subcortical brain structures in three groups of individuals with different CAG triplet expansions: ≤26 (normal), 27–35 (intermediate), and &gt;40 (full penetrance). The structures evaluated include the amygdala (<b>A</b>,<b>F</b>), caudate (<b>B</b>,<b>G</b>), pallidum (<b>C</b>,<b>H</b>), putamen (<b>D</b>,<b>I</b>), and thalamus (<b>E</b>,<b>J</b>), in both the left and right hemispheres. The <span class="html-italic">p</span> values indicate the statistical significance of the observed differences: * (<span class="html-italic">p</span> &lt; 0.002), ** (<span class="html-italic">p</span> &lt; 0.0002), and **** (<span class="html-italic">p</span> &lt; 0.000001).</p> Full article ">Figure 2 Cont.
<p>Subcortical structure volumes according to CAG triplet expansion. This figure compares the volumes of various subcortical brain structures in three groups of individuals with different CAG triplet expansions: ≤26 (normal), 27–35 (intermediate), and &gt;40 (full penetrance). The structures evaluated include the amygdala (<b>A</b>,<b>F</b>), caudate (<b>B</b>,<b>G</b>), pallidum (<b>C</b>,<b>H</b>), putamen (<b>D</b>,<b>I</b>), and thalamus (<b>E</b>,<b>J</b>), in both the left and right hemispheres. The <span class="html-italic">p</span> values indicate the statistical significance of the observed differences: * (<span class="html-italic">p</span> &lt; 0.002), ** (<span class="html-italic">p</span> &lt; 0.0002), and **** (<span class="html-italic">p</span> &lt; 0.000001).</p> Full article ">Figure 3
<p>Ventricular system volumes according to CAG triplet expansion. This figure compares the volumes in three groups of individuals with different CAG triplet expansions: ≤26 (normal), 27–35 (intermediate), and &gt;40 (full penetrance). The evaluated structures include the 4th ventricle (<b>A</b>) and supratentorial ventricle (<b>B</b>). The <span class="html-italic">p</span> values indicate the statistical significance of the observed differences: (*** <span class="html-italic">p</span> &lt; 0.00001, **** <span class="html-italic">p</span> &lt; 0.000001).</p> Full article ">Figure 4
<p>Comparison of infratentorial structure volumes according to CAG triplet expansion. This figure compares the volumes of infratentorial structures in three groups of individuals with different CAG triplet expansions: ≤26 (normal), 27–35 (intermediate), and &gt;40 (full penetrance). The evaluated structures include the left cerebellar white matter volume (<b>A</b>), right cerebellar white matter (<b>B</b>), left cerebellar gray matter (<b>C</b>), right cerebellar, gray matter (<b>D</b>), and brainstem (<b>E</b>). The <span class="html-italic">p</span> values indicate the statistical significance of the observed differences: (* <span class="html-italic">p</span> &lt; 0.002), ** <span class="html-italic">p</span> &lt; 0.0002).</p> Full article ">Figure 5
<p>Cortical and hippocampal volumes according to CAG triplet expansion. This figure compares the volumes of various cortical areas and the hippocampus in three groups of individuals with different CAG triplet expansions: ≤26 (normal), 27–35 (intermediate), and &gt;40 (full penetrance). The evaluated structures include the frontal cortex (<b>A</b>), insular cortex (<b>B</b>), occipital cortex (<b>C</b>), parietal cortex (<b>D</b>), temporal cortex (<b>E</b>), left hippocampus (<b>F</b>), and right hippocampus (<b>G</b>). The <span class="html-italic">p</span> values indicate the statistical significance of the observed differences: (<span class="html-italic">p</span> &gt; 0.05).</p> Full article ">Scheme 1
<p>Brain Volumetry via Nuclear Magnetic Resonance Imaging in Individuals with CAG Triplet Expansion.</p> Full article ">
14 pages, 2046 KiB  
Article
Hyperchloremia and Hypernatremia Decreased Microglial and Neuronal Survival during Oxygen–Glucose Deprivation/Reperfusion
by Reetika Mahajan, Faheem Shehjar, Adnan I. Qureshi and Zahoor A. Shah
Biomedicines 2024, 12(3), 551; https://doi.org/10.3390/biomedicines12030551 - 29 Feb 2024
Viewed by 1521
Abstract
Hyperchloremia and hypernatremia are associated with higher mortality in ischemic stroke, but it remains unclear whether their influence directly contributes to ischemic injury. We investigated the impact of 0.9% sodium chloride (154 mM NaCl), 0.9% sodium acetate (167 mM CH3COONa), and [...] Read more.
Hyperchloremia and hypernatremia are associated with higher mortality in ischemic stroke, but it remains unclear whether their influence directly contributes to ischemic injury. We investigated the impact of 0.9% sodium chloride (154 mM NaCl), 0.9% sodium acetate (167 mM CH3COONa), and their different combinations (3:1, 2:1, and 1:1) on microglial (HMC-3) and neuronal (differentiated SH-SY5Y) survival during oxygen–glucose deprivation/reperfusion (OGD/R). Further, we assessed the effect of hyperchloremia and hypernatremia-treated and OGD/R-induced HMC-3-conditioned media on differentiated SH-SY5Y cells under OGD/R conditions. We performed cell viability, cell toxicity, and nitric oxide (NO) release assays and studied the alteration in expression of caspase-1 and caspase-3 in different cell lines when exposed to hyperchloremia and hypernatremia. Cell survival was decreased in 0.9% NaCl, 0.9% CH3COONa, combinations of HMC-3 and differentiated SH-SY5Y, and differentiated SH-SY5Y cells challenged with HMC-3-conditioned media under normal and OGD/R conditions. Under OGD/R conditions, differentiated SH-SY5Y cells were less likely to survive exposure to 0.9% NaCl. Expression of caspase-1 and caspase-3 in HMC-3 and differentiated SH-SY5Y cells was altered when exposed to 0.9% NaCl, 0.9% CH3COONa, and their combinations. A total of 0.9% NaCl and 0.9% CH3COONa and their combinations decreased the NO production in HMC-3 cells under normal and OGD/R conditions. Both hypernatremia and hyperchloremia reduced the survival of HMC-3 and differentiated SH-SY5Y cells under OGD/R conditions. Based on the OGD/R in vitro model that mimics human ischemic stroke conditions, it possibly provides a link for the increased death associated with hyperchloremia or hypernatremia in stroke patients. Full article
(This article belongs to the Special Issue Brain Injury and Neurodegeneration: Molecular, Functional, and Translational Approach 3.0)
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Figure 1

Figure 1
<p>The impact of hyperchloremia and hypernatremia on cell viability, cell toxicity, and caspase-1 and -3 expression in hypoxia-induced HMC-3 cells. (<b>a</b>) Cell viability (<span class="html-italic">n</span> = 4); (<b>b</b>) cell toxicity (<span class="html-italic">n</span> = 3) of HMC-3 cells treated with 0.9% NaCl, 0.9% CH<sub>3</sub>COONa, and three different combinations (3:1, 2:1, and 1:1) of 0.9% NaCl and 0.9% CH<sub>3</sub>COONa, respectively, under normal and OGD/R induction. (<b>c</b>) The expression levels of caspase-1 and -3 were analyzed by WB. (<b>d</b>,<b>e</b>) The relative quantification of caspase-1 and caspase-3 proteins under normal and OGD/R conditions. The blots (<span class="html-italic">n</span> = 3) were quantified by ImageJ software and normalized with β-actin. The statistical significance was determined by a two-way ANOVA, and significant differences (<span class="html-italic">p</span> &lt; 0.05, <span class="html-italic">p</span> &lt; 0.01, <span class="html-italic">p</span> &lt; 0.001, and <span class="html-italic">p</span> &lt; 0.0001) are symbolized as *, **, ***, and ****, respectively.</p> Full article ">Figure 2
<p>The impact of hyperchloremia and hypernatremia on caspase-3 expression and cell viability in normal and OGD/R-induced differentiated SH-SY5Y cells. (<b>a</b>) Cell viability (<span class="html-italic">n</span> = 4), (<b>b</b>) Cell cytotoxicity (<span class="html-italic">n</span> = 3) of differentiated SH-SY5Y cells exposed to 0.9% NaCl, 0.9% CH<sub>3</sub>COONa, and three different NaCl:CH<sub>3</sub>COONa ratios (3:1, 2:1, and 1:1) under both normal and OGD/R conditions, compared to the control. (<b>c</b>) Caspase-3 expression levels were analyzed by WB. (<b>d</b>) Relative quantification of caspase-3 protein levels was conducted under normal and OGD/R conditions. Quantification of blots (<span class="html-italic">n</span> = 3) was performed using ImageJ software and normalized to β-tubulin. Statistical significance was determined through two-way ANOVA, with significance levels denoted as follows: *, <span class="html-italic">p</span> &lt; 0.05; **, <span class="html-italic">p</span> &lt; 0.01; ***, <span class="html-italic">p</span> &lt; 0.001; ****, <span class="html-italic">p</span> &lt; 0.0001.</p> Full article ">Figure 3
<p>The effect of 0.9% NaCl, 0.9% CH<sub>3</sub>COONa, and different combinations of 0.9% NaCl and 0.9% CH<sub>3</sub>COONa treatment on cell viability, cell cytotoxicity, and caspase expression in OGD/R-induced differentiated SH-SY5Y conditioned with OGD/R-induced HMC-3 media. (<b>a</b>) Cell viability (<span class="html-italic">n</span> = 4) and (<b>b</b>) cell cytotoxicity (<span class="html-italic">n</span> = 3) of treated differentiated SH-SY5Y cells were further exposed to conditioned HMC-3 cell media for 24 h under normal and OGD/R conditions. (<b>c</b>) The expression levels of caspase-1 and -3 were analyzed by WB. (<b>d</b>,<b>e</b>) Different treatments of 0.9% NaCl and 0.9% CH<sub>3</sub>COONa significantly changed the caspase-1 and -3 expression in challenged SHSY-5Y cells with HMC-3-conditioned media as compared to the control. The blots (<span class="html-italic">n</span> = 3) were quantified with ImageJ software and normalized with β-actin. The significance was determined by a two-way ANOVA, and significant differences (<span class="html-italic">p</span> &lt; 0.05, <span class="html-italic">p</span> &lt; 0.01, <span class="html-italic">p</span> &lt; 0.001, and <span class="html-italic">p</span> &lt; 0.0001) are symbolized as *, **, ***, and ****, respectively.</p> Full article ">Figure 4
<p>Impact of 0.9% NaCl, 0.9% CH<sub>3</sub>COONa, and various combinations of these treatments on nitric oxide (NO) release in HMC-3 and SHSY-5Y cells exposed to HMC-3-conditioned media under normal and OGD/R conditions (<span class="html-italic">n</span> = 3). (<b>a</b>,<b>b</b>) A significant decrease in the release of NO in various treatments as compared to control under normal and OGD/R in HMC-3 cells. (<b>c</b>,<b>d</b>) There was a significant change in NO release in various treatments in SHSY-5Y cells exposed to HMC-3-conditioned media compared to the control under normal and OGD/R conditions. The significance was determined by a two-way ANOVA, and significant differences (<span class="html-italic">p</span> &lt; 0.05, <span class="html-italic">p</span> &lt; 0.01, <span class="html-italic">p</span> &lt; 0.001, and <span class="html-italic">p</span> &lt; 0.0001) are symbolized as *, **, ***, and ****, respectively.</p> Full article ">
16 pages, 1767 KiB  
Article
Association between Serum GDF-15 and Cognitive Dysfunction in Hemodialysis Patients
by Hae Ri Kim, Moo Jun Kim, Jae Wan Jeon, Young Rok Ham, Ki Ryang Na, Hyerim Park, Jwa-Jin Kim and Dae Eun Choi
Biomedicines 2024, 12(2), 358; https://doi.org/10.3390/biomedicines12020358 - 3 Feb 2024
Cited by 1 | Viewed by 1490
Abstract
Cognitive dysfunction is more frequent in end-stage renal disease (ESRD) patients undergoing hemodialysis compared with the healthy population, emphasizing the need for early detection. Interest in serum markers that reflect cognitive function has recently increased. Elevated serum growth differentiation factor 15 (GDF-15) levels [...] Read more.
Cognitive dysfunction is more frequent in end-stage renal disease (ESRD) patients undergoing hemodialysis compared with the healthy population, emphasizing the need for early detection. Interest in serum markers that reflect cognitive function has recently increased. Elevated serum growth differentiation factor 15 (GDF-15) levels are known to be associated with an increased risk of decreased renal function and cognitive dysfunction. This study investigated the relationship between GDF-15 and cognitive dysfunction in hemodialysis patients using a retrospective analysis of 92 individuals aged ≥ 18 years. Cognitive function was assessed using the Korean version of the Mini-Mental Status Examination (K-MMSE), categorizing patients into normal (≥24 points) and cognitive dysfunction (<24 points). As a result, serum GDF-15 concentrations were at significantly higher levels in the cognitive dysfunction group (7500.42 pg/mL, p = 0.001). Logistic regression indicated an increased risk of K-MMSE scores < 24 points when serum GDF-15 exceeded 5408.33 pg/mL. After indoxyl sulfate exposure in HT22 cells, HT22 cells survival was decreased and GDF-15 expression in HT22 cells was increased. Similarly, exposure to indoxyl sulfate in mouse brain tissue resulted in an increased expression of GDF-15. This study highlights the potential of serum GDF-15 as a marker for cognitive dysfunction in hemodialysis patients, offering a valuable screening tool. Serum GDF-15 is related to cognitive dysfunction in hemodialysis patients and may be helpful in screening for cognitive dysfunction in hemodialysis patients. Full article
(This article belongs to the Special Issue Brain Injury and Neurodegeneration: Molecular, Functional, and Translational Approach 3.0)
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Figure 1

Figure 1
<p>Correlation between K-MMSE score and the clinical parameters. GDF-15 = growth and differentiation factor 15; CRP = C-reactive protein.</p> Full article ">Figure 2
<p>ROC curve linking the GDF-15 level to a K-MMSE score &lt; 24. A serum GDF-15 level &gt; 5408.33 pg/mL exhibited 63.6% sensitivity and 64.4% specificity when distinguishing between normal and mild to severe cognitive dysfunction.</p> Full article ">Figure 3
<p>Renal function in an ischemia–reperfusion-induced renal injury (IRI) model. s-Creatinine = serum creatinine; Control = sham; AZO = renal ischemia–reperfusion-induced azotemia; BUN = blood urea nitrogen. * <span class="html-italic">p</span> value &lt; 0.05, Control (sham) vs. AZO (IRI).</p> Full article ">Figure 4
<p>GDF-15 levels in the brain tissue of mice with azotemia induced by ischemia–reperfusion injury (IRI). α-tubulin was used as the control. Control = sham; AZO = IRI. * <span class="html-italic">p</span> &lt; 0.05, Control (sham) vs. AZO (IRI model).</p> Full article ">Figure 5
<p>Survival of mouse hippocampal neuronal cell line HT22 following indoxyl sulfate treatment at concentrations of 1, 5, and 10 mM. IS = indoxyl sulfate. * <span class="html-italic">p</span> &lt; 0.05, control vs. indoxyl sulfate (IS) 5 mM, # <span class="html-italic">p</span> &lt; 0.05, control vs. IS 10 mM.</p> Full article ">Figure 6
<p>GDF-15 level in mouse hippocampal neuronal cell line HT22 following indoxyl sulfate treatment. GDF-15 expression increased in a concentration-dependent manner. α-tubulin was used as the control. Con, control, GDF-15 = growth and differentiation factor-15, IS = indoxyl sulfate. * <span class="html-italic">p</span> &lt; 0.05, control vs. IS 5 mM, ** <span class="html-italic">p</span> &lt; 0.05, control vs. IS 5 mM, # <span class="html-italic">p</span> &lt; 0.05, control vs. IS 10 mM.</p> Full article ">
20 pages, 10423 KiB  
Article
Next-Generation Proteomics of Brain Extracellular Vesicles in Schizophrenia Provide New Clues on the Altered Molecular Connectome
by Cristina Lorca, María Fernández-Rhodes, Jose Antonio Sánchez Milán, María Mulet, Félix Elortza, Alfredo Ramos-Miguel, Luis F. Callado, J. Javier Meana, Maria Mur, Iolanda Batalla, Elisabet Vilella, Aida Serra and Xavier Gallart-Palau
Biomedicines 2024, 12(1), 129; https://doi.org/10.3390/biomedicines12010129 - 8 Jan 2024
Cited by 3 | Viewed by 2663
Abstract
Extracellular vesicles (EVs) are tiny membranous structures that mediate intercellular communication. The role(s) of these vesicles have been widely investigated in the context of neurological diseases; however, their potential implications in the neuropathology subjacent to human psychiatric disorders remain mostly unknown. Here, by [...] Read more.
Extracellular vesicles (EVs) are tiny membranous structures that mediate intercellular communication. The role(s) of these vesicles have been widely investigated in the context of neurological diseases; however, their potential implications in the neuropathology subjacent to human psychiatric disorders remain mostly unknown. Here, by using next-generation discovery-driven proteomics, we investigate the potential role(s) of brain EVs (bEVs) in schizophrenia (SZ) by analyzing these vesicles from the three post-mortem anatomical brain regions: the prefrontal cortex (PFC), hippocampus (HC), and caudate (CAU). The results obtained indicate that bEVs from SZ-affected brains contain region-specific proteins that are associated with abnormal GABAergic and glutamatergic transmission. Similarly, these vesicles from the analyzed regions were implicated in synaptic decay, abnormal brain immunity, neuron structural imbalances, and impaired cell homeostasis. Our findings also provide evidence, for the first time, that networks of molecular exchange (involving the PFC, HC, and CAU) are potentially active and mediated by EVs in non-diseased brains. Additionally, these bEV-mediated networks seem to have become partially reversed and largely disrupted in the brains of subjects affected by SZ. Taken as a whole, these results open the door to the uncovering of new biological markers and therapeutic targets, based on the compositions of bEVs, for the benefit of patients affected by SZ and related psychotic disorders. Full article
(This article belongs to the Special Issue Brain Injury and Neurodegeneration: Molecular, Functional, and Translational Approach 3.0)
►▼ Show Figures

Figure 1

Figure 1
<p>Morphological and ultrastructural characterization of brain extracellular vesicles (bEVs) obtained from post-mortem brain tissues. (<b>A</b>) Average size distribution profiles of bEVs obtained using nanoparticle tracking analysis (NTA) of bEVs from the prefrontal cortex (PFC) region of controls (C) and subjects with schizophrenia (SZ). Captures refer to the average distribution obtained from ten independent size/concentration distribution runs. Standard deviation of the mean is shaded in blue. (<b>B</b>) Representative micrographs of bEVs, obtained by transmission electron microscopy (TEM) from the PFC, hippocampus (HC), and caudate (CAU) regions of C subjects (upper micrographs) and of subjects with SZ (lower micrographs). Scale bar in <a href="#biomedicines-12-00129-f001" class="html-fig">Figure 1</a>B represents 100 nm. ** indicates significant statistical differences (<span class="html-italic">p</span> &lt; 0.0001).</p> Full article ">Figure 2
<p>Molecular characterization performed by four-dimensional liquid chromatography proteomics of brain extracellular vesicles (bEVs) of the three analyzed brain regions, prefrontal cortex (PFC), hippocampus (HC), and caudate (CAU). (<b>A</b>,<b>B</b>) Presence of microvesicle markers in the proteomes of bEVs obtained from subjects with schizophrenia (SZ) and control (C) subjects. Parallel analysis of the obtained proteome data was performed in (<b>A</b>) with the top 100 protein markers curated in the specialized microvesicle data repository, Vesiclepedia, and in (<b>B</b>), it was performed with the specialized exosomal data repository, Exocarta. (<b>C</b>) Diagram table indicating the number of common and unique proteins present in the bEV proteomes of the analyzed brain regions, PFC, HC, and CAU, from C subjects and subjects with SZ. Salmon tones represent common proteins to the PFC region. Purple tones represent common proteins to the HC region, and blue tones represent common proteins to the CAU region. ALL indicates the number of proteins commonly present in the three evaluated regions, and ANY indicates the total number of proteins considering all identified proteins between the three evaluated regions. (<b>D</b>) Mean average cumulative proteome levels in bEVs of the three analyzed brain regions, PFC, HC, and CAU, from C subjects and subjects with SZ. *** indicates statistical significance at <span class="html-italic">p</span> &lt; 0.001. Error bars represent standard deviation of the mean.</p> Full article ">Figure 3
<p>Depiction of the disorder-specific modulation, identified by four-dimensional proteomics, affecting the molecular compositions of brain extracellular vesicles (bEVs) in the three analyzed brain regions (prefrontal cortex (PFC), hippocampus (HC), and caudate (CAU)) of subjects with schizophrenia (SZ). (<b>A</b>) Heatmap showing significant modulation of bEV proteins from each, respectively, analyzed brain region of SZ brains. Proteins are indicated by gene symbol. (<b>B</b>) Sectorial graph showing the molecular functional classification of the proteins significantly modulated in bEVs of subjects with SZ. (<b>C</b>) Sectorial graph showing the biological process classification of the proteins significantly modulated in bEVs of subjects with SZ. (<b>D</b>) Sectorial graphs showing molecular functional classification (outer graph circle) and biological process classification (inner graph circle) of the proteins significantly modulated in bEVs of subjects with SZ obtained from the analyzed brain regions (PFC, HC, and CAU). Upper sectorial graphs depict significantly upregulated bEV proteins, whereas lower sectorial graphs depict significantly downregulated bEV proteins. ° symbol in the heatmap indicates significance <span class="html-italic">p</span> &lt; 0.001; ☆ symbol in the heatmap indicates significance by Bonferroni corrected <span class="html-italic">p</span>-value (<span class="html-italic">p</span> &lt; 0.05).</p> Full article ">Figure 4
<p>Interaction analysis of brain extracellular vesicle (bEV) proteins identified in the analyzed brain regions (prefrontal cortex (PFC), hippocampus (HC), and caudate (CAU)) of the controls (C) and subjects with schizophrenia (SZ). Proteins are represented collectively in three triangle diagrams per condition (C and SZ) for display purposes. Brain regions are represented at the triangle apexes. Lines in blue and red between apexes indicate strong positive correlation and strong negative correlation, respectively, for each specific protein in bEVs between brain regions (connected apexes). Only proteins significantly modulated (<span class="html-italic">p</span> &lt; 0.05) in bEVs of subjects with SZ were included in the analysis, and only strong correlations (r ≥ ±0.8) are depicted.</p> Full article ">Figure 5
<p>Advanced pathway analysis of the connectome proteins in bEVs identified as changed in SZ brains considering the three analyzed regions. Proteins were subjected to advanced pathway bioinformatic analysis in R through clusterprofiler in enrichGO package.</p> Full article ">
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