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Molecular Biomarkers in Neurodevelopmental and Neurodegenerative Disorders
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Molecular Biomarkers in Neurodevelopmental and Neurodegenerative Disorders

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 (20 October 2022) | Viewed by 54494

Special Issue Editor

Dr. Marwa Zafarullah

E-Mail Website
Guest Editor
College of Biological Sciences, University of California Davis, Davis, CA 95817, USA
Interests: neurodegenerative disorders; genetics; rare complex syndromes; FXTAS; genomics; biomarker discovery; FXS; next-generation sequencing; Intellectual disability
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Today, neurodevelopmental and neurodegenerative diseases represent significant causes of death in industrialized economies. The development of unique targeted therapeutics for these disorders faces many challenges, including the lack of biomarkers for early diagnosis and progression, complicated molecular mechanisms, heterogeneous phenotypes, limited historical data, and difficulty in assessing efficacy in clinical trials for which small patient populations limit enrollment. Thus, it is of importance to identify biomarkers that can provide fast, objective evidence for changes in underlying disease pathophysiology, which may, in turn, be used for clinical benefit.

It is our pleasure to announce a new Special Issue of the International Journal of Molecular Sciences on “Molecular Biomarkers in Neurodevelopmental and Neurodegenerative Disorders”. With this Special Issue, we intend to collect both original contributions and review articles focused on the:

  1. Research directed at the development of molecular biomarkers for the early diagnosis and detection of the progression of neurodevelopmental or neurodegenerative disorders;
  2. The investigation of the underlying molecular mechanisms, with the aim of identifying molecular signatures, leading to targeted therapeutics;
  3. Research leading to new therapeutic approaches that could help in biomarker discovery and that are currently in clinical testing.

Since IJMS is a journal of molecular science, pure clinical studies will not be suitable; however, clinical submissions with biomolecular experiments focusing on the topics mentioned above are welcomed. We encourage you to reach out to us if you have any questions.

Dr. Marwa Zafarullah
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

  • neurodevelopmental disorders
  • neurodegenerative disorders
  • biomarker discovery
  • molecular biology
  • human genetics

Published Papers (17 papers)

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16 pages, 5806 KiB  
Article
Effects of β-amyloid (1-42) Administration on the Main Neurogenic Niches of the Adult Brain: Amyloid-Induced Neurodegeneration Influences Neurogenesis
by Konstantin Yenkoyan, Tigran Margaryan, Senik Matinyan, Vergine Chavushyan, Margarita Danielyan, Tigran Davtyan and Michail Aghajanov
Int. J. Mol. Sci. 2022, 23(23), 15444; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232315444 - 06 Dec 2022
Cited by 2 | Viewed by 2017
Abstract
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and warrants further study as well as timely treatment. Additionally, the mechanisms of the brain’s intrinsic defense against chronic injury are not yet fully understood. Herein, we examined the response of the main neurogenic [...] Read more.
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and warrants further study as well as timely treatment. Additionally, the mechanisms of the brain’s intrinsic defense against chronic injury are not yet fully understood. Herein, we examined the response of the main neurogenic niches to amyloid exposure and the associated changes in structure and synaptic activity. Flow cytometry of Nestin-, Vimentin-, Nestin/Vimentin-, NeuN-, GFAP-, NeuN/GFAP-, NSE-, BrdU-, Wnt-, BrdU/Wnt-, VEGF-, Sox14-, VEGF/Sox14-, Sox10-, Sox2-, Sox10/Sox2-, Bax-, and Bcl-xL-positive cells was performed in the subventricular zone (SVZ), hippocampus, and cerebral cortex of rat brains on 90th day after intracerebroventricular (i.c.v.) single injection of a fraction of β-amyloid (Aβ) (1-42). The relative structural changes in these areas and disruptions to synaptic activity in the entorhinal cortex–hippocampus circuit were also evaluated. Our flow analyses revealed a reduction in the numbers of Nestin-, Vimentin-, and Nestin/Vimentin-positive cells in neurogenic niches and the olfactory bulb. These changes were accompanied by an increased number of BrdU-positive cells in the hippocampus and SVZ. The latter changes were strongly correlated with changes in the numbers of VEGF- and VEGF/Sox14-positive cells. The morphological changes were characterized by significant neural loss, a characteristic shift in entorhinal cortex–hippocampus circuit activity, and decreased spontaneous alternation in a behavioral test. We conclude that although an injection of Aβ (1-42) induced stem cell proliferation and triggered neurogenesis at a certain stage, this process was incomplete and led to neural stem cell immaturity. We propose the idea of enhancing adult neurogenesis as a promising strategy for preventing dementia at healthy elderly people andpeople at high risk for developing AD, or treating patients diagnosed with AD. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Neurodevelopmental and Neurodegenerative Disorders)
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22 pages, 2956 KiB  
Article
Plasma Neurofilament Light Chain (NF-L) Is a Prognostic Biomarker for Cortical Damage Evolution but Not for Cognitive Impairment or Epileptogenesis Following Experimental TBI
by Mette Heiskanen, Olli Jääskeläinen, Eppu Manninen, Shalini Das Gupta, Pedro Andrade, Robert Ciszek, Olli Gröhn, Sanna-Kaisa Herukka, Noora Puhakka and Asla Pitkänen
Int. J. Mol. Sci. 2022, 23(23), 15208; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232315208 - 02 Dec 2022
Cited by 4 | Viewed by 1598
Abstract
Plasma neurofilament light chain (NF-L) levels were assessed as a diagnostic biomarker for traumatic brain injury (TBI) and as a prognostic biomarker for somatomotor recovery, cognitive decline, and epileptogenesis. Rats with severe TBI induced by lateral fluid-percussion injury (n = 26, 13 with [...] Read more.
Plasma neurofilament light chain (NF-L) levels were assessed as a diagnostic biomarker for traumatic brain injury (TBI) and as a prognostic biomarker for somatomotor recovery, cognitive decline, and epileptogenesis. Rats with severe TBI induced by lateral fluid-percussion injury (n = 26, 13 with and 13 without epilepsy) or sham-operation (n = 8) were studied. During a 6-month follow-up, rats underwent magnetic resonance imaging (MRI) (day (D) 2, D7, and D21), composite neuroscore (D2, D6, and D14), Morris-water maze (D35–D39), and a 1-month-long video-electroencephalogram to detect unprovoked seizures during the 6th month. Plasma NF-L levels were assessed using a single-molecule assay at baseline (i.e., naïve animals) and on D2, D9, and D178 after TBI or a sham operation. Plasma NF-L levels were 483-fold higher on D2 (5072.0 ± 2007.0 pg/mL), 89-fold higher on D9 (930.3 ± 306.4 pg/mL), and 3-fold higher on D176 32.2 ± 8.9 pg/mL after TBI compared with baseline (10.5 ± 2.6 pg/mL; all p < 0.001). Plasma NF-L levels distinguished TBI rats from naïve animals at all time-points examined (area under the curve [AUC] 1.0, p < 0.001), and from sham-operated controls on D2 (AUC 1.0, p < 0.001). Plasma NF-L increases on D2 were associated with somatomotor impairment severity (ρ = −0.480, p < 0.05) and the cortical lesion extent in MRI (ρ = 0.401, p < 0.05). Plasma NF-L increases on D2 or D9 were associated with the cortical lesion extent in histologic sections at 6 months post-injury (ρ = 0.437 for D2; ρ = 0.393 for D9, p < 0.05). Plasma NF-L levels, however, did not predict somatomotor recovery, cognitive decline, or epileptogenesis (p > 0.05). Plasma NF-L levels represent a promising noninvasive translational diagnostic biomarker for acute TBI and a prognostic biomarker for post-injury somatomotor impairment and long-term structural brain damage. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Neurodevelopmental and Neurodegenerative Disorders)
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14 pages, 1668 KiB  
Article
Potential of Non-Coding RNA as Biomarkers for Progressive Supranuclear Palsy
by Fabio A. Simoes, Greig Joilin, Oliver Peters, Luisa-Sophie Schneider, Josef Priller, Eike Jakob Spruth, Ina Vogt, Okka Kimmich, Annika Spottke, Daniel C. Hoffmann, Björn Falkenburger, Moritz Brandt, Johannes Prudlo, Kathrin Brockmann, Franca Laura Fries, James B. Rowe, Alistair Church, Gesine Respondek, Sarah F. Newbury, P. Nigel Leigh, Huw R. Morris, Günter U. Höglinger and Majid Hafezparastadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2022, 23(23), 14554; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314554 - 22 Nov 2022
Viewed by 1818
Abstract
Objective markers for the neurodegenerative disorder progressive supranuclear palsy (PSP) are needed to provide a timely diagnosis with greater certainty. Non-coding RNA (ncRNA), including microRNA, piwi-interacting RNA, and transfer RNA, are good candidate markers in other neurodegenerative diseases, but have not been investigated [...] Read more.
Objective markers for the neurodegenerative disorder progressive supranuclear palsy (PSP) are needed to provide a timely diagnosis with greater certainty. Non-coding RNA (ncRNA), including microRNA, piwi-interacting RNA, and transfer RNA, are good candidate markers in other neurodegenerative diseases, but have not been investigated in PSP. Therefore, as proof of principle, we sought to identify whether they were dysregulated in matched serum and cerebrospinal fluid (CSF) samples of patients with PSP. Small RNA-seq was undertaken on serum and CSF samples from healthy controls (n = 20) and patients with PSP (n = 31) in two cohorts, with reverse transcription-quantitative PCR (RT-qPCR) to confirm their dysregulation. Using RT-qPCR, we found in serum significant down-regulation in hsa-miR-92a-3p, hsa-miR-626, hsa-piR-31068, and tRNA-ValCAC. In CSF, both hsa-let-7a-5p and hsa-piR-31068 showed significant up-regulation, consistent with their changes observed in the RNA-seq results. Interestingly, we saw no correlation in the expression of hsa-piR-31068 within our matched serum and CSF samples, suggesting there is no common dysregulatory mechanism between the two biofluids. While these changes were in a small cohort of samples, we have provided novel evidence that ncRNA in biofluids could be possible diagnostic biomarkers for PSP and further work will help to expand this potential. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Neurodevelopmental and Neurodegenerative Disorders)
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11 pages, 1909 KiB  
Article
Leukocyte Telomere Length as Potential Biomarker of HD Progression: A Follow-Up Study
by Daniela Scarabino, Liana Veneziano, Elide Mantuano, Ivan Arisi, Alessia Fiore, Marina Frontali and Rosa Maria Corbo
Int. J. Mol. Sci. 2022, 23(21), 13449; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232113449 - 03 Nov 2022
Cited by 3 | Viewed by 1253
Abstract
The identification of biomarkers for neurodegenerative disorders such as Huntington’s disease (HD) is crucial for monitoring disease progression and therapeutic trial outcomes, especially in the pre-manifest disease stage (pre-HD). In a previous study, we observed that leukocyte telomere length (LTL) was strongly correlated [...] Read more.
The identification of biomarkers for neurodegenerative disorders such as Huntington’s disease (HD) is crucial for monitoring disease progression and therapeutic trial outcomes, especially in the pre-manifest disease stage (pre-HD). In a previous study, we observed that leukocyte telomere length (LTL) was strongly correlated with the estimated time to clinical onset in pre-HD subjects. To validate this hypothesis, we designed a follow-up study in which we analyzed LTL in 45 pre-HD stage subjects at baseline (T0) and then again after clinical onset at follow-up (T1); the follow-up interval was about 3 years, and the CAG range was 39–51 repeats; 90 peripheral blood mononuclear cell samples (PBMCs) were obtained from the Enroll-HD biorepository. In pre-HD subjects at T0, LTL was significantly reduced by 22% compared to the controls and by 14% from T0 at T1. No relationship was observed between the LTL and CAG numbers in subjects carrying different CAG repeats at T0 and at T1, suggesting that LTL reduction occurs independently of CAG number in pre-HD subjects. ROC curve analysis was used to test the validity of LTL as a potential biomarker of HD progression and showed that LTL measurement is extremely accurate in discriminating pre-HD subjects from the controls and even pre-HD from manifest HD, thus yielding a robust prognostic value in pre-HD subjects. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Neurodevelopmental and Neurodegenerative Disorders)
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18 pages, 4013 KiB  
Article
Cluster Analysis of Short Sensory Profile Data Reveals Sensory-Based Subgroups in Autism Spectrum Disorder
by Ariel M. Lyons-Warren, Michael F. Wangler and Ying-Wooi Wan
Int. J. Mol. Sci. 2022, 23(21), 13030; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232113030 - 27 Oct 2022
Cited by 3 | Viewed by 1920
Abstract
Autism spectrum disorder is a common, heterogeneous neurodevelopmental disorder lacking targeted treatments. Additional features include restricted, repetitive patterns of behaviors and differences in sensory processing. We hypothesized that detailed sensory features including modality specific hyper- and hypo-sensitivity could be used to identify clinically [...] Read more.
Autism spectrum disorder is a common, heterogeneous neurodevelopmental disorder lacking targeted treatments. Additional features include restricted, repetitive patterns of behaviors and differences in sensory processing. We hypothesized that detailed sensory features including modality specific hyper- and hypo-sensitivity could be used to identify clinically recognizable subgroups with unique underlying gene variants. Participants included 378 individuals with a clinical diagnosis of autism spectrum disorder who contributed Short Sensory Profile data assessing the frequency of sensory behaviors and whole genome sequencing results to the Autism Speaks’ MSSNG database. Sensory phenotypes in this cohort were not randomly distributed with 10 patterns describing 43% (162/378) of participants. Cross comparison of two independent cluster analyses on sensory responses identified six distinct sensory-based subgroups. We then characterized subgroups by calculating the percent of patients in each subgroup who had variants with a Combined Annotation Dependent Depletion (CADD) score of 15 or greater in each of 24,896 genes. Each subgroup exhibited a unique pattern of genes with a high frequency of variants. These results support the use of sensory features to identify autism spectrum disorder subgroups with shared genetic variants. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Neurodevelopmental and Neurodegenerative Disorders)
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11 pages, 7168 KiB  
Article
Circulating U13 Small Nucleolar RNA as a Potential Biomarker in Huntington’s Disease: A Pilot Study
by Silvia Romano, Carmela Romano, Martina Peconi, Alessia Fiore, Gianmarco Bellucci, Emanuele Morena, Fernanda Troili, Virginia Cipollini, Viviana Annibali, Simona Giglio, Rosella Mechelli, Michela Ferraldeschi, Liana Veneziano, Elide Mantuano, Gabriele Sani, Andrea Vecchione, Renato Umeton, Franco Giubilei, Marco Salvetti, Rosa Maria Corbo, Daniela Scarabino and Giovanni Ristoriadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2022, 23(20), 12440; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012440 - 18 Oct 2022
Cited by 1 | Viewed by 1569
Abstract
Plasma small RNAs have been recently explored as biomarkers in Huntington’s disease (HD). We performed an exploratory study on nine HD patients, eight healthy subjects (HS), and five psychiatric patients (PP; to control for iatrogenic confounder effects) through an Affymetrix-Gene-Chip-miRNA-Array. We validated the [...] Read more.
Plasma small RNAs have been recently explored as biomarkers in Huntington’s disease (HD). We performed an exploratory study on nine HD patients, eight healthy subjects (HS), and five psychiatric patients (PP; to control for iatrogenic confounder effects) through an Affymetrix-Gene-Chip-miRNA-Array. We validated the results in an independent population of 23 HD, 15 pre-HD, 24 PP, 28 Alzheimer’s disease (AD) patients (to control the disease-specificity) and 22 HS through real-time PCR. The microarray results showed higher levels of U13 small nucleolar RNA (SNORD13) in HD patients than controls (fold change 1.54, p = 0.003 HD vs. HS, and 1.44, p = 0.0026 HD vs. PP). In the validation population, a significant increase emerged with respect to both pre-HD and the control groups (p < 0.0001). SNORD13 correlated with the status of the mutant huntingtin carrier (r = 0.73; p < 0.001) and the disease duration (r = 0.59; p = 0.003). The receiver operating characteristic (ROC) curve analysis showed the high accuracy of SNORD13 in discriminating HD patients from other groups (AUC = 0.963). An interactome and pathway analysis on SNORD13 revealed enrichments for factors relevant to HD pathogenesis. We report the unprecedented finding of a potential disease-specific role of SNORD13 in HD. It seems to peripherally report a ‘tipping point’ in the pathogenic cascade at the neuronal level. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Neurodevelopmental and Neurodegenerative Disorders)
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13 pages, 4387 KiB  
Article
Microglial CD74 Expression Is Regulated by TGFβ Signaling
by Jannik Jahn, Antonia Bollensdorf, Christopher Kalischer, Robin Piecha, Jana Weiß-Müller, Phani Sankar Potru, Tamara Ruß and Björn Spittau
Int. J. Mol. Sci. 2022, 23(18), 10247; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810247 - 06 Sep 2022
Cited by 4 | Viewed by 1839
Abstract
Microglia play important roles during physiological and pathological situations in the CNS. Several reports have described the expression of Cd74 in disease-associated and aged microglia. Here, we demonstrated that TGFβ1 controled the expression of Cd74 in microglia in vitro and in vivo. Using [...] Read more.
Microglia play important roles during physiological and pathological situations in the CNS. Several reports have described the expression of Cd74 in disease-associated and aged microglia. Here, we demonstrated that TGFβ1 controled the expression of Cd74 in microglia in vitro and in vivo. Using BV2 cells, primary microglia cultures as well as Cx3cr1CreERT2:R26-YFP:Tgfbr2fl/fl in combination with qPCR, flow cytometry, and immunohistochemistry, we were able to provide evidence that TGFβ1 inhibited LPS-induced upregulation of Cd74 in microglia. Interestingly, TGFβ1 alone was able to mediate downregulation of CD74 in vitro. Moreover, silencing of TGFβ signaling in vivo resulted in marked upregulation of CD74, further underlining the importance of microglial TGFβ signaling during regulation of microglia activation. Taken together, our data indicated that CD74 is a marker for activated microglia and further demonstrated that microglial TGFβ signaling is important for regulation of Cd74 expression during microglia activation. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Neurodevelopmental and Neurodegenerative Disorders)
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12 pages, 1193 KiB  
Article
Differences in Expression of IQSEC2 Transcript Isoforms in Male and Female Cases with Loss of Function Variants and Neurodevelopmental Disorder
by Beatriz Baladron, Lidia M. Mielu, Estrella López-Martín, Maria J. Barrero, Lidia Lopez, Jose I. Alvarado, Sara Monzón, Sarai Varona, Isabel Cuesta, Rosario Cazorla, Julián Lara, Gemma Iglesias, Enriqueta Román, Purificación Ros, Gema Gomez-Mariano, Isabel Cubillo, Esther Hernandez-San Miguel, Daniel Rivera, Javier Alonso, Eva Bermejo-Sánchez, Manuel Posada and Beatriz Martínez-Delgadoadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2022, 23(16), 9480; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23169480 - 22 Aug 2022
Cited by 3 | Viewed by 1941
Abstract
Pathogenic hemizygous or heterozygous mutations in the IQSEC2 gene cause X-linked intellectual developmental disorder-1 (XLID1), characterized by a variable phenotype including developmental delay, intellectual disability, epilepsy, hypotonia, autism, microcephaly and stereotypies. It affects both males and females typically through loss of function in [...] Read more.
Pathogenic hemizygous or heterozygous mutations in the IQSEC2 gene cause X-linked intellectual developmental disorder-1 (XLID1), characterized by a variable phenotype including developmental delay, intellectual disability, epilepsy, hypotonia, autism, microcephaly and stereotypies. It affects both males and females typically through loss of function in males and haploinsufficiency in heterozygous females. Females are generally less affected than males. Two novel unrelated cases, one male and one female, with de novo IQSEC2 variants were detected by trio-based whole exome sequencing. The female case had a previously undescribed frameshift mutation (NM_001111125:c.3300dup; p.Met1101Tyrfs*5), and the male showed an intronic variant in intron 6, with a previously unknown effect (NM_001111125:c.2459+21C>T). IQSEC2 gene expression study revealed that this intronic variant created an alternative donor splicing site and an aberrant product, with the inclusion of 19bp, confirming the pathogenic effect of the intron variant. Moreover, a strong reduction in the expression of the long, but also the short IQSEC2 isoforms, was detected in the male correlating with a more severe phenotype, while the female case showed no decreased expression of the short isoform, and milder effects of the disease. This suggests that the abnormal expression levels of the different IQSEC2 transcripts could be implicated in the severity of disease manifestations. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Neurodevelopmental and Neurodegenerative Disorders)
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20 pages, 6222 KiB  
Article
Partial Endothelial Nitric Oxide Synthase Deficiency Exacerbates Cognitive Deficit and Amyloid Pathology in the APPswe/PS1ΔE9 Mouse Model of Alzheimer’s Disease
by Sara Ahmed, Yu Jing, Bruce G. Mockett, Hu Zhang, Wickliffe C. Abraham and Ping Liu
Int. J. Mol. Sci. 2022, 23(13), 7316; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137316 - 30 Jun 2022
Cited by 5 | Viewed by 2099
Abstract
Increasing evidence implicates endothelial dysfunction in the pathogenesis of Alzheimer’s disease (AD). Nitric oxide (NO) derived from endothelial NO synthase (eNOS) is essential in maintaining cerebrovascular function and can modulate the production and clearance of amyloid beta (Aβ). APPswe/PSdE1 (APP/PS1) mice display age-related [...] Read more.
Increasing evidence implicates endothelial dysfunction in the pathogenesis of Alzheimer’s disease (AD). Nitric oxide (NO) derived from endothelial NO synthase (eNOS) is essential in maintaining cerebrovascular function and can modulate the production and clearance of amyloid beta (Aβ). APPswe/PSdE1 (APP/PS1) mice display age-related Aβ accumulation and memory deficits. In order to make the model more clinically relevant with an element of endothelial dysfunction, we generated APP/PS1/eNOS+/− mice by crossing complete eNOS deficient (eNOS−/−) mice and APP/PS1 mice. APP/PS1/eNOS+/− mice at 8 months of age displayed a more severe spatial working memory deficit relative to age-matched APP/PS1 mice. Moreover, immunohistochemistry and immunoblotting revealed significantly increased Aβ plaque load in the brains of APP/PS1/eNOS+/− mice, concomitant with upregulated BACE-1 (hence increased Aβ production), downregulated insulin-degrading enzyme (hence reduced Aβ clearance) and increased immunoreactivity and expression of microglia. The present study, for the first time, demonstrated that partial eNOS deficiency exacerbated behavioral dysfunction, Aβ brain deposition, and microglial pathology in APP/PS1 mice, further implicating endothelial dysfunction in the pathogenesis of AD. The present findings also provide the scientific basis for developing preventive and/or therapeutic strategies by targeting endothelial dysfunction. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Neurodevelopmental and Neurodegenerative Disorders)
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24 pages, 2876 KiB  
Article
Altered Brain Arginine Metabolism and Polyamine System in a P301S Tauopathy Mouse Model: A Time-Course Study
by Hannah Mein, Yu Jing, Faraz Ahmad, Hu Zhang and Ping Liu
Int. J. Mol. Sci. 2022, 23(11), 6039; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23116039 - 27 May 2022
Cited by 2 | Viewed by 2065
Abstract
Altered arginine metabolism (including the polyamine system) has recently been implicated in the pathogenesis of tauopathies, characterised by hyperphosphorylated and aggregated microtubule-associated protein tau (MAPT) accumulation in the brain. The present study, for the first time, systematically determined the time-course of arginine metabolism [...] Read more.
Altered arginine metabolism (including the polyamine system) has recently been implicated in the pathogenesis of tauopathies, characterised by hyperphosphorylated and aggregated microtubule-associated protein tau (MAPT) accumulation in the brain. The present study, for the first time, systematically determined the time-course of arginine metabolism changes in the MAPT P301S (PS19) mouse brain at 2, 4, 6, 8 and 12 months of age. The polyamines putrescine, spermidine and spermine are critically involved in microtubule assembly and stabilization. This study, therefore, further investigated how polyamine biosynthetic and catabolic enzymes changed in PS19 mice. There were general age-dependent increases of L-arginine, L-ornithine, putrescine and spermidine in the PS19 brain (particularly in the hippocampus and parahippocampal region). While this profile change clearly indicates a shift of arginine metabolism to favor polyamine production (a polyamine stress response), spermine levels were decreased or unchanged due to the upregulation of polyamine retro-conversion pathways. Our results further implicate altered arginine metabolism (particularly the polyamine system) in the pathogenesis of tauopathies. Given the role of the polyamines in microtubule assembly and stabilization, future research is required to understand the functional significance of the polyamine stress response and explore the preventive and/or therapeutic opportunities for tauopathies by targeting the polyamine system. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Neurodevelopmental and Neurodegenerative Disorders)
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20 pages, 3426 KiB  
Article
Huntingtin Co-Isolates with Small Extracellular Vesicles from Blood Plasma of TgHD and KI-HD Pig Models of Huntington’s Disease and Human Blood Plasma
by Hanadi Ananbeh, Jaromir Novak, Stefan Juhas, Jana Juhasova, Jiri Klempir, Kristyna Doleckova, Irena Rysankova, Karolina Turnovcova, Jaroslav Hanus, Hana Hansikova, Petr Vodicka and Helena Kupcova Skalnikova
Int. J. Mol. Sci. 2022, 23(10), 5598; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105598 - 17 May 2022
Cited by 15 | Viewed by 3459
Abstract
(1) Background: Huntington’s disease (HD) is rare incurable hereditary neurodegenerative disorder caused by CAG repeat expansion in the gene coding for the protein huntingtin (HTT). Mutated huntingtin (mHTT) undergoes fragmentation and accumulation, affecting cellular functions and leading to neuronal cell death. Porcine models [...] Read more.
(1) Background: Huntington’s disease (HD) is rare incurable hereditary neurodegenerative disorder caused by CAG repeat expansion in the gene coding for the protein huntingtin (HTT). Mutated huntingtin (mHTT) undergoes fragmentation and accumulation, affecting cellular functions and leading to neuronal cell death. Porcine models of HD are used in preclinical testing of currently emerging disease modifying therapies. Such therapies are aimed at reducing mHTT expression, postpone the disease onset, slow down the progression, and point out the need of biomarkers to monitor disease development and therapy efficacy. Recently, extracellular vesicles (EVs), particularly exosomes, gained attention as possible carriers of disease biomarkers. We aimed to characterize HTT and mHTT forms/fragments in blood plasma derived EVs in transgenic (TgHD) and knock-in (KI-HD) porcine models, as well as in HD patients’ plasma. (2) Methods: Small EVs were isolated by ultracentrifugation and HTT forms were visualized by western blotting. (3) Results: The full length 360 kDa HTT co-isolated with EVs from both the pig model and HD patient plasma. In addition, a ~70 kDa mutant HTT fragment was specific for TgHD pigs. Elevated total huntingtin levels in EVs from plasma of HD groups compared to controls were observed in both pig models and HD patients, however only in TgHD were they significant (p = 0.02). (4) Conclusions: Our study represents a valuable initial step towards the characterization of EV content in the search for HD biomarkers. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Neurodevelopmental and Neurodegenerative Disorders)
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12 pages, 2040 KiB  
Article
Decoding the Synaptic Proteome with Long-Term Exposure to Midazolam during Early Development
by Nghi M. Nguyen, Neetha N. Vellichirammal, Chittibabu Guda and Gurudutt Pendyala
Int. J. Mol. Sci. 2022, 23(8), 4137; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23084137 - 08 Apr 2022
Cited by 5 | Viewed by 2273
Abstract
The intensive use of anesthetic and sedative agents in the neonatal intensive care unit (NICU) has raised controversial concerns about the potential neurodevelopmental risks. This study focused on midazolam (MDZ), a common benzodiazepine regularly used as a sedative on neonates in the NICU. [...] Read more.
The intensive use of anesthetic and sedative agents in the neonatal intensive care unit (NICU) has raised controversial concerns about the potential neurodevelopmental risks. This study focused on midazolam (MDZ), a common benzodiazepine regularly used as a sedative on neonates in the NICU. Mounting evidence suggests a single exposure to MDZ during the neonatal period leads to learning disturbances. However, a knowledge gap that remains is how long-term exposure to MDZ during very early stages of life impacts synaptic alterations. Using a preclinical rodent model system, we mimicked a dose-escalation regimen on postnatal day 3 (P3) pups until day 21. Next, purified synaptosomes from P21 control and MDZ animals were subjected to quantitative mass-spectrometry-based proteomics, to identify potential proteomic signatures. Further analysis by ClueGO identified enrichment of proteins associated with actin-binding and protein depolymerization process. One potential hit identified was alpha adducin (ADD1), belonging to the family of cytoskeleton proteins, which was upregulated in the MDZ group and whose expression was further validated by Western blot. In summary, this study sheds new information on the long-term exposure of MDZ during the early stages of development impacts synaptic function, which could subsequently perturb neurobehavioral outcomes at later stages of life. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Neurodevelopmental and Neurodegenerative Disorders)
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Review

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16 pages, 861 KiB  
Review
Activation of the Monocyte/Macrophage System and Abnormal Blood Levels of Lymphocyte Subpopulations in Individuals with Autism Spectrum Disorder: A Systematic Review and Meta-Analysis
by Gara Arteaga-Henríquez, Jorge Lugo-Marín, Laura Gisbert, Imanol Setién-Ramos, Mónica Martínez-Gallo, Ricardo Pujol-Borrell and Josep Antoni Ramos-Quiroga
Int. J. Mol. Sci. 2022, 23(22), 14329; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232214329 - 18 Nov 2022
Cited by 9 | Viewed by 2500
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental condition with a so far unknown etiology. Increasing evidence suggests that a state of systemic low-grade inflammation may be involved in the pathophysiology of this condition. However, studies investigating peripheral blood levels of immune cells, and/or [...] Read more.
Autism spectrum disorder (ASD) is a neurodevelopmental condition with a so far unknown etiology. Increasing evidence suggests that a state of systemic low-grade inflammation may be involved in the pathophysiology of this condition. However, studies investigating peripheral blood levels of immune cells, and/or of immune cell activation markers such as neopterin are lacking and have provided mixed findings. We performed a systematic review and meta-analysis of studies comparing total and differential white blood cell (WBC) counts, blood levels of lymphocyte subpopulations and of neopterin between individuals with ASD and typically developing (TD) controls (PROSPERO registration number: CRD CRD42019146472). Online searches covered publications from 1 January 1994 until 1 March 2022. Out of 1170 publication records identified, 25 studies were finally included. Random-effects meta-analyses were carried out, and sensitivity analyses were performed to control for potential moderators. Results: Individuals with ASD showed a significantly higher WBC count (k = 10, g = 0.29, p = 0.001, I2 = 34%), significantly higher levels of neutrophils (k = 6, g = 0.29, p = 0.005, I2 = 31%), monocytes (k = 11, g = 0.35, p < 0.001, I2 = 54%), NK cells (k = 7, g = 0.36, p = 0.037, I2 = 67%), Tc cells (k = 4, g = 0.73, p = 0.021, I2 = 82%), and a significantly lower Th/Tc cells ratio (k = 3, g = −0.42, p = 0.008, I2 = 0%), compared to TD controls. Subjects with ASD were also characterized by a significantly higher neutrophil-to-lymphocyte ratio (NLR) (k = 4, g = 0.69, p = 0.040, I2 = 90%), and significantly higher neopterin levels (k = 3, g = 1.16, p = 0.001, I2 = 97%) compared to TD controls. No significant differences were found with respect to the levels of lymphocytes, B cells, Th cells, Treg cells, and Th17 cells. Sensitivity analysis suggested that the findings for monocyte and neutrophil levels were robust, and independent of other factors, such as medication status, diagnostic criteria applied, and/or the difference in age or sex between subjects with ASD and TD controls. Taken together, our findings suggest the existence of a chronically (and systemically) activated inflammatory response system in, at least, a subgroup of individuals with ASD. This might have not only diagnostic, but also, therapeutic implications. However, larger longitudinal studies including more homogeneous samples and laboratory assessment methods and recording potential confounding factors such as body mass index, or the presence of comorbid psychiatric and/or medical conditions are urgently needed to confirm the findings. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Neurodevelopmental and Neurodegenerative Disorders)
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36 pages, 4957 KiB  
Review
Neuro-Inflammation Modulation and Post-Traumatic Brain Injury Lesions: From Bench to Bed-Side
by Alice Jacquens, Edward J. Needham, Elisa R. Zanier, Vincent Degos, Pierre Gressens and David Menon
Int. J. Mol. Sci. 2022, 23(19), 11193; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911193 - 23 Sep 2022
Cited by 15 | Viewed by 4593
Abstract
Head trauma is the most common cause of disability in young adults. Known as a silent epidemic, it can cause a mosaic of symptoms, whether neurological (sensory–motor deficits), psychiatric (depressive and anxiety symptoms), or somatic (vertigo, tinnitus, phosphenes). Furthermore, cranial trauma (CT) in [...] Read more.
Head trauma is the most common cause of disability in young adults. Known as a silent epidemic, it can cause a mosaic of symptoms, whether neurological (sensory–motor deficits), psychiatric (depressive and anxiety symptoms), or somatic (vertigo, tinnitus, phosphenes). Furthermore, cranial trauma (CT) in children presents several particularities in terms of epidemiology, mechanism, and physiopathology—notably linked to the attack of an immature organ. As in adults, head trauma in children can have lifelong repercussions and can cause social and family isolation, difficulties at school, and, later, socio-professional adversity. Improving management of the pre-hospital and rehabilitation course of these patients reduces secondary morbidity and mortality, but often not without long-term disability. One hypothesized contributor to this process is chronic neuroinflammation, which could accompany primary lesions and facilitate their development into tertiary lesions. Neuroinflammation is a complex process involving different actors such as glial cells (astrocytes, microglia, oligodendrocytes), the permeability of the blood–brain barrier, excitotoxicity, production of oxygen derivatives, cytokine release, tissue damage, and neuronal death. Several studies have investigated the effect of various treatments on the neuroinflammatory response in traumatic brain injury in vitro and in animal and human models. The aim of this review is to examine the various anti-inflammatory therapies that have been implemented. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Neurodevelopmental and Neurodegenerative Disorders)
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22 pages, 732 KiB  
Review
Molecular Biomarkers and Their Implications for the Early Diagnosis of Selected Neurodegenerative Diseases
by Julia Doroszkiewicz, Magdalena Groblewska and Barbara Mroczko
Int. J. Mol. Sci. 2022, 23(9), 4610; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094610 - 21 Apr 2022
Cited by 22 | Viewed by 4267
Abstract
The degeneration and dysfunction of neurons are key features of neurodegenerative diseases (NDs). Currently, one of the main challenges facing researchers and clinicians is the ability to obtain reliable diagnostic tools that will allow for the diagnosis of NDs as early as possible [...] Read more.
The degeneration and dysfunction of neurons are key features of neurodegenerative diseases (NDs). Currently, one of the main challenges facing researchers and clinicians is the ability to obtain reliable diagnostic tools that will allow for the diagnosis of NDs as early as possible and the detection of neuronal dysfunction, preferably in the presymptomatic stage. Additionally, better tools for assessing disease progression in this group of disorders are also being sought. The ideal biomarker must have high sensitivity and specificity, be easy to measure, give reproducible results, and reflect the disease progression. Molecular biomarkers include miRNAs and extracellular microvesicles known as exosomes. They may be measured in two extracellular fluids of the highest importance in NDs, i.e., cerebrospinal fluid (CSF) and blood. The aim of the current review is to summarize the pathophysiology of the four most frequent NDs—i.e., Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS)—as well as current progress in the research into miRNAs as biomarkers in these major neurodegenerative diseases. In addition, we discuss the possibility of using miRNA-based therapies in the treatment of neurodegenerative diseases, and present the limitations of this type of therapy. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Neurodevelopmental and Neurodegenerative Disorders)
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10 pages, 486 KiB  
Review
Immune Response Modifications in the Genetic Forms of Parkinson’s Disease: What Do We Know?
by Luca Magistrelli, Elena Contaldi, Francesca Vignaroli, Silvia Gallo, Federico Colombatto, Roberto Cantello and Cristoforo Comi
Int. J. Mol. Sci. 2022, 23(7), 3476; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073476 - 23 Mar 2022
Cited by 6 | Viewed by 1978
Abstract
Parkinson’s disease (PD) is a common neurodegenerative disease characterized by loss of dopaminergic neurons in the pars compacta of the midbrain substantia nigra. PD pathophysiology is complex, multifactorial, and not fully understood yet. Nonetheless, recent data show that immune system hyperactivation with [...] Read more.
Parkinson’s disease (PD) is a common neurodegenerative disease characterized by loss of dopaminergic neurons in the pars compacta of the midbrain substantia nigra. PD pathophysiology is complex, multifactorial, and not fully understood yet. Nonetheless, recent data show that immune system hyperactivation with concomitant production of pro-inflammatory cytokines, both in the central nervous system (CNS) and the periphery, is a signature of idiopathic PD. About 5% of PD patients present an early onset with a determined genetic cause, with either autosomal dominant or recessive inheritance. The involvement of immunity in the genetic forms of PD has been a matter of interest in several recent studies. In this review, we will summarize the main findings of this new and promising field of research Full article
(This article belongs to the Special Issue Molecular Biomarkers in Neurodevelopmental and Neurodegenerative Disorders)
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20 pages, 725 KiB  
Review
Fragile X Syndrome: From Molecular Aspect to Clinical Treatment
by Dragana D. Protic, Ramkumar Aishworiya, Maria Jimena Salcedo-Arellano, Si Jie Tang, Jelena Milisavljevic, Filip Mitrovic, Randi J. Hagerman and Dejan B. Budimirovic
Int. J. Mol. Sci. 2022, 23(4), 1935; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23041935 - 09 Feb 2022
Cited by 24 | Viewed by 15017
Abstract
Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by the full mutation as well as highly localized methylation of the fragile X mental retardation 1 (FMR1) gene on the long arm of the X chromosome. Children with FXS are commonly [...] Read more.
Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by the full mutation as well as highly localized methylation of the fragile X mental retardation 1 (FMR1) gene on the long arm of the X chromosome. Children with FXS are commonly co-diagnosed with Autism Spectrum Disorder, attention and learning problems, anxiety, aggressive behavior and sleep disorder, and early interventions have improved many behavior symptoms associated with FXS. In this review, we performed a literature search of original and review articles data of clinical trials and book chapters using MEDLINE (1990–2021) and ClinicalTrials.gov. While we have reviewed the biological importance of the fragile X mental retardation protein (FMRP), the FXS phenotype, and current diagnosis techniques, the emphasis of this review is on clinical interventions. Early non-pharmacological interventions in combination with pharmacotherapy and targeted treatments aiming to reverse dysregulated brain pathways are the mainstream of treatment in FXS. Overall, early diagnosis and interventions are fundamental to achieve optimal clinical outcomes in FXS. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Neurodevelopmental and Neurodegenerative Disorders)
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