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Molecular Research of Neurodegenerative and Psychiatric Diseases, 2nd Edition

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

Deadline for manuscript submissions: 30 June 2025 | Viewed by 1896

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Dr. Dubravka Švob Štrac

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Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Rudjer Boskovic Institute, Bijenicka cesta 54, 10 000 Zagreb, Croatia
Interests: molecular basis; genetics; psychiatric disorders; neurodegenerative diseases; pharmacogenetics; neurobiology; neuropharmacology
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Dear Colleagues,

Neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis and Huntington’s disease, as well as psychiatric diseases, such as schizophrenia, anxiety, depression and addictions, are multifactorial and heterogeneous disorders, which pose significant health, social and economic problems. Despite many studies, their complex etiology is still poorly understood, and therapeutic strategies are often limited to relieving their symptoms. The elucidation of their molecular background may contain keys for identifying risk factors, offering novel diagnostic or prognostic biomarkers, as well as providing novel and specific targets for their prevention and treatment. This Special Issue aims to present the most up-to-date findings regarding research targeting molecular mechanisms underlying different neurodegenerative and psychiatric diseases. It aims to provide a broad overview of novel advances in the field, including studies at the molecular, epi/genetic and cellular levels, but will also cover integrative, imaging and psychopharmacology research areas, as well as comprehensive omics approaches. We welcome the submission of studies using various preclinical in vitro and in vivo models, as well as clinical studies involving human subjects.

Dr. Dubravka Švob Štrac
Guest Editor

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Keywords

neurodegenerative disorders
psychiatric diseases
biomarkers
therapeutic targets
omics approaches
molecular pathways
cell biology
animal models
clinical studies

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25 pages, 2329 KiB

Open AccessArticle

Genomic Characterisation of the Relationship and Causal Links Between Vascular Calcification, Alzheimer’s Disease, and Cognitive Traits

by Emmanuel O. Adewuyi and Simon M. Laws

Biomedicines 2025, 13(3), 618; https://doi.org/10.3390/biomedicines13030618 - 3 Mar 2025

Viewed by 205

Abstract

Background/Objectives: Observational studies suggest a link between vascular calcification and dementia or cognitive decline, but the evidence is conflicting, and the underlying mechanisms are unclear. Here, we investigate the shared genetic and causal relationships of vascular calcification—coronary artery calcification (CAC) and abdominal aortic calcification (AAC)—with Alzheimer’s disease (AD), and five cognitive traits. Methods: We analyse large-scale genome-wide association studies (GWAS) summary statistics, using well-regarded methods, including linkage disequilibrium score regression (LDSC), Mendelian randomisation (MR), pairwise GWAS (GWAS-PW), and gene-based association analysis. Results: Our findings reveal a nominally significant positive genome-wide genetic correlation between CAC and AD, which becomes non-significant after excluding the APOE region. CAC and AAC demonstrate significant negative correlations with cognitive performance and educational attainment. MR found no causal association between CAC or AAC and AD or cognitive traits, except for a bidirectional borderline-significant association between AAC and fluid intelligence scores. Pairwise-GWAS analysis identifies no shared causal SNPs (posterior probability of association [PPA]3 < 0.5). However, we find pleiotropic loci (PPA4 > 0.9), particularly on chromosome 19, with gene association analyses revealing significant genes in shared regions, including APOE, TOMM40, NECTIN2, and APOC1. Moreover, we identify suggestively significant loci (PPA4 > 0.5) on chromosomes 1, 6, 7, 9 and 19, implicating pleiotropic genes, including NAV1, IPO9, PHACTR1, UFL1, FHL5, and FOCAD. Conclusions: Current findings reveal limited genetic correlation and no significant causal associations of CAC and AAC with AD or cognitive traits. However, significant pleiotropic loci, particularly at the APOE region, highlight the complex interplay between vascular calcification and neurodegenerative processes. Given APOE’s roles in lipid metabolism, neuroinflammation, and vascular integrity, its involvement may link vascular and neurodegenerative disorders, pointing to potential targets for further investigation. Full article

(This article belongs to the Special Issue Molecular Research of Neurodegenerative and Psychiatric Diseases, 2nd Edition)

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Figure 1

Figure 1
Schematic representation of MR assumptions and study design. The figure provides an overview of the MR analysis approach, emphasising its application and core assumptions in examining the potential causal relationship between exposure and outcome variables [<a href="#B28-biomedicines-13-00618" class="html-bibr">28</a>,<a href="#B29-biomedicines-13-00618" class="html-bibr">29</a>,<a href="#B30-biomedicines-13-00618" class="html-bibr">30</a>,<a href="#B31-biomedicines-13-00618" class="html-bibr">31</a>]. It highlights the three fundamental assumptions of MR: (1) the genetic variants (SNPs) used as instrumental variables must be robustly associated with the exposure, (2) these SNPs should not be associated with confounding factors (we note the direction of the arrow as recently illustrated [<a href="#B47-biomedicines-13-00618" class="html-bibr">47</a>]), and (3) they must influence the outcome exclusively through the exposure [<a href="#B28-biomedicines-13-00618" class="html-bibr">28</a>,<a href="#B29-biomedicines-13-00618" class="html-bibr">29</a>,<a href="#B30-biomedicines-13-00618" class="html-bibr">30</a>,<a href="#B31-biomedicines-13-00618" class="html-bibr">31</a>]. The figure also details the clumping parameters employed to ensure the independence and relevance of the genetic instruments. The analysis involves two rounds: first using CAC and AAC as exposures against AD and cognitive traits as outcomes, and the reverse analysis where AD and cognitive traits serve as exposures, with CAC and AAC as the outcome variables. AAC: abdominal aortic calcification, AD: Alzheimer’s disease, CAC: coronary artery calcification, EA: effect allele, IVW: inverse variance weighted, MR: Mendelian randomisation, MR-PRESSO: Mendelian randomization pleiotropy residual sum and outlier, NEA: non-effect allele, SNP: single nucleotide polymorphism. Full article ">Figure 2
Causal effect of CAC on AD and cognitive traits. CAC: coronary artery calcification, CI: confidence interval, IVW: inverse variance weighted, nIV: number of instrumental variables, OR: odds ratio, p: p-value, cExecutive function: common executive function. Full article ">Figure 3
Causal effect of AAC onAD and cognitive traits. AAC: abdominal aortic calcification, CI: confidence interval, IVW: inverse variance weighted, nIV: number of instrumental variables, OR: odds ratio, p: p-value, cExecutive function: common executive function. Full article ">Figure 4
Causal effect of AD on cognitive traits against CAC. CAC: coronary artery calcification, CI: confidence interval, IVW: inverse variance weighted, nIV: number of instrumental variables, OR: odds ratio, p: p-value, cExecutive function: common executive function. Full article ">Figure 5
Causal effect of AD and cognitive traits on AAC. AAC: abdominal aortic calcification, CI: confidence interval, IVW: inverse variance weighted, nIV: number of instrumental variables, OR: odds ratio, p: p-value, cExecutive function: common executive function. Full article ">

19 pages, 3121 KiB

Open AccessArticle

Neuroprotective Effects of Dehydroepiandrosterone Sulphate Against Aβ Toxicity and Accumulation in Cellular and Animal Model of Alzheimer’s Disease

by Barbara Vuic, Tina Milos, Erika Kvak, Marcela Konjevod, Lucija Tudor, Szidónia Farkas, Gordana Nedic Erjavec, Matea Nikolac Perkovic, Dora Zelena and Dubravka Svob Strac

Biomedicines 2025, 13(2), 432; https://doi.org/10.3390/biomedicines13020432 - 11 Feb 2025

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Abstract

Background/Objectives: Beneficial effects of neurosteroid dehydroepiandrosterone sulphate (DHEAS) on cognition, emotions and behavior have been previously reported, suggesting its potential in the prevention and treatment of various neuropsychiatric and neurodegenerative disorders, including Alzheimer’s disease (AD). This study aimed to investigate the potential neuroprotective actions of DHEAS against Aβ toxicity in both cellular and animal models of AD. Methods: After optimizing the AD model in vitro, we investigated the DHEAS effects on the viability and death of primary mouse neurons exposed to toxic Aβ₄₂ oligomers for 24 h. In order to extend our research to an in vivo study, we further tested the acute effects of intraperitoneal DHEAS administration on the Aβ plaque density in different brain regions of 3xTg-AD mice, an animal model of AD. Results: In cell culture, DHEAS hampered the decrease in the neuronal viability caused by toxic Aβ oligomers, primarily by influencing mitochondrial function and apoptosis. DHEAS also counteracted the increase in the mRNA expression of selected genes (PI3K, Akt, Bcl2, Bax), induced in neuronal culture by treatment with Aβ₄₂ oligomers. Obtained data suggested the involvement of mitochondria, caspases 3 and 7, as well as the PI3K/Akt and Bcl2 signaling network in the antiapoptotic properties of DHEAS in neurons. Forty-eight hours after DHEAS treatment, a significantly lower number of Aβ plaques was observed in the motor cortex but not in other brain areas of 3xTg-AD mice. Conclusions: Results indicated potential neuroprotective effects of DHEAS against Aβ toxicity and accumulation, suggesting that DHEAS supplementation should be further studied as a novel option for AD prevention and/or treatment. Full article

(This article belongs to the Special Issue Molecular Research of Neurodegenerative and Psychiatric Diseases, 2nd Edition)

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Figure 1

Figure 1
Treatment with various concentrations (0.1–10 μM) of Aβ42 monomers, oligomers and polymers for 24 h affected the viability of primary mouse neurons determined by (A) MTT Assay: * p < 0.005, ** p < 0.0001 vs. control; (B) RealTime-Glo™ MT Assay: * p < 0.002, ** p < 0.0001 vs. control; and demonstrated that 10 μM Aβ42 oligomers were most toxic, as confirmed with (C) MUSE Count and Viability reagent using MUSE™ cell analyzer: ** p < 0.0001 vs. control. Results are expressed as means ± SD from 3 experiments and analyzed by ANOVA followed by Tukey’s multiple comparisons test. Dots represent individual values. Full article ">Figure 2
Treatment with various (0.1–10 μM) concentrations of Aβ42 oligomers for (A) 24 h (B) 48 h and (C) 72 h, affected the viability of primary mouse neurons determined by MTT assay: * p < 0.01, ** p < 0.001 vs. control, and demonstrated significant neurotoxicity already after 24 h treatment with Aβ42 oligomers. Results are expressed as means ± SD from 4 to 6 experiments and analyzed by ANOVA followed by Tukey’s multiple comparisons test. Dots represent individual values. Full article ">Figure 3
Treatment of primary mouse neurons with various (0.1–10 μM) concentrations of Aβ42 oligomers for 24 h affected (A) ATP levels: * p < 0.05 vs. control; (B) cell membrane integrity: ** p < 0.001 vs. control; (C) caspase 3/7 activity: * p < 0.02 vs. control; determined by Mitochondrial ToxGlo™ Assay and Caspase-Glo® 3/7 Assay™. Results are expressed as means ± SD from 3 experiments and analyzed by ANOVA followed by Tukey’s multiple comparisons test. Dots represent individual values. Full article ">Figure 4
A representative sample of the cell Bcl-2 activation profile in primary mouse neurons treated for 24 h with (A) vehicle (control) (B) 10 μM Aβ42 oligomers, obtained by using MUSE Bcl-2 activation reagent and the MUSE™ cell analyzer, and (C) Bcl-2 activation levels expressed as means ± SD from 3 experiments and analyzed by the Student t-test: ** p < 0.001 vs. control. Dots represent individual values. Full article ">Figure 5
Effects of various DHEAS concentrations on the viability of primary mouse neurons treated with 10 μM Aβ42 oligomers for 24 h determined by (A) MTT Assay: ** p < 0.0001 vs. control, φ p < 0.01 vs. Aβ42 oligomers; (B) RealTime-Glo MT Assay: * p < 0.02 vs. control, φ p < 0.01 or p < 0.05 vs. Aβ42 oligomers. Results are expressed as means ± SD from 3 experiments and analyzed by ANOVA followed by Tukey’s multiple comparisons test. Dots represent individual values. Full article ">Figure 6
Effects of 10−7 M DHEAS on mitochondrial dysfunction, apoptosis and necrosis of primary mouse neurons treated with 10 μM Aβ42 oligomers for 24 h, determined by (A) Hoechst 33342 (blue) and propidium iodide (red) staining and EVOS system, Scale bar 100 μm; (B) ** p < 0.005 vs. Aβ42 oligomers, analyzed by two-way ANOVA followed by Tukey’s multiple comparisons test; and determined by Mitochondrial ToxGlo™ measuring (C) ATP levels: ** p < 0.003 vs. Aβ42 oligomers, analyzed by Student’s t-test and (D) cell membrane integrity. Results are expressed as means ± SD from 3 experiments. Dots represent individual values. Full article ">Figure 7
Effects of 10−7 M DHEAS administration in the primary mouse neuronal culture treated with 10 μM Aβ42 oligomers for 24 h on (A) caspase 3/7 activity determined with Caspase-Glo® 3/7 Assay. *** p < 0.0005 vs. control, φ p < 0.004 vs. Aβ42 oligomers; (B) mRNA expression of selected genes (PI3K, Akt, Bcl2, Bax, Bax/Bcl2 ratio) determined by qPCR and normalized to GAPDH expression. * p < 0.02, ** p < 0.001, **** p < 0.0001 vs. control; φ p < 0.002, φφ p < 0.0001 vs. Aβ42 oligomers. Results are expressed as means ± SD from 3–4 experiments and analyzed by one or two-way ANOVA followed by Tukey’s multiple comparisons test. Full article ">Figure 8
The effects of 10 mg/kg DHEAS on Aβ plaque density in the mouse motor cortex (MC) of 3xTg-AD mice 24 and 48 h after i.p. administration. (A) MC representative immunohistochemistry staining against Aβ, Scale bar 100 μm; (B) analyzed brain slices from MC; (C) relative number of Aβ plaques in the MC of 3xTg-AD mice 24 h and 48 h following vehicle (Control) or 10 mg/kg DHEAS i.p. administration: ** p < 0.002 vs. control, φ p < 0.03 vs. DHEAS 24 h group. Results are expressed as means ± SD from 6 mice per group and analyzed by two-way ANOVA followed by Tukey’s multiple comparisons test. Dots represent individual values. Full article ">

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14 pages, 692 KiB

Open AccessSystematic Review

Fibromyalgia, Depression, and Autoimmune Disorders: An Interconnected Web of Inflammation

by Stefania Sedda, Maria Piera L. Cadoni, Serenella Medici, Elena Aiello, Gian Luca Erre, Alessandra Matilde Nivoli, Ciriaco Carru and Donatella Coradduzza

Biomedicines 2025, 13(2), 503; https://doi.org/10.3390/biomedicines13020503 - 18 Feb 2025

Viewed by 527

Abstract

Background: Fibromyalgia, depression, and autoimmune diseases represent a triad of interconnected conditions characterized by overlapping biological pathways, including chronic inflammation, immune dysregulation, and neurochemical imbalances. Understanding their shared mechanisms offers opportunities for innovative therapeutic approaches. Objective: This systematic review explores the common inflammatory- and immune-related pathways among these conditions, emphasizing their implications for biomarker development and novel therapeutic strategies. Methods: Following PRISMA guidelines, a comprehensive literature search was conducted in databases including PubMed, Scopus, Web of Science, and the Cochrane Library. Studies examining the relationship between fibromyalgia, depression, and autoimmune diseases with a focus on immune responses, inflammatory biomarkers, and therapeutic interventions were included. The quality of the selected studies was assessed using the Cochrane Risk of Bias tool. Results: From the 255 identified studies, 12 met the inclusion criteria. Evidence supports the role of pro-inflammatory cytokines (e.g., IL-6, TNF-α) and neurochemical dysregulation (e.g., serotonin, dopamine) as key factors in the pathophysiology of these conditions. Pilot studies highlight the potential of immune-modulating therapies, including low-dose IL-2 and anti-inflammatory agents such as N-acetylcysteine and minocycline, in alleviating both physical and psychological symptoms. Emerging biomarkers, including cytokine profiles and platelet serotonin activity, show promise for personalized treatment approaches. Conclusions: The shared inflammatory pathways linking fibromyalgia, depression, and autoimmune diseases underscore the need for integrated therapeutic strategies. Although pilot studies provide preliminary insights, validation through large-scale, multicenter trials is essential. Future research should focus on standardizing methodologies and leveraging biomarker-driven precision medicine to improve outcomes for patients with these complex, multifactorial conditions. Full article

(This article belongs to the Special Issue Molecular Research of Neurodegenerative and Psychiatric Diseases, 2nd Edition)

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