Advances in Diagnostics, Brain Delivery Systems and Therapeutics of Neurodegenerative Disease

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biomolecules biomolecules	5.5	8.3	2011	16.9 Days	CHF 2700	Submit
International Journal of Molecular Sciences ijms	5.6	7.8	2000	16.3 Days	CHF 2900	Submit
Molecules molecules	4.6	6.7	1996	14.6 Days	CHF 2700	Submit
Pharmaceutics pharmaceutics	5.4	6.9	2009	14.2 Days	CHF 2900	Submit

15 pages, 693 KiB

Open AccessReview

Switching On/Off Amyloid Plaque Formation in Transgenic Animal Models of Alzheimer’s Disease

by Sergey A. Kozin, Olga I. Kechko, Alexei A. Adzhubei, Alexander A. Makarov and Vladimir A. Mitkevich

Int. J. Mol. Sci. 2024, 25(1), 72; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25010072 - 20 Dec 2023

Cited by 1 | Viewed by 1453

Abstract

A hallmark of Alzheimer’s disease (AD) are the proteinaceous aggregates formed by the amyloid-beta peptide (Aβ) that is deposited inside the brain as amyloid plaques. The accumulation of aggregated Aβ may initiate or enhance pathologic processes in AD. According to the amyloid hypothesis, [...] Read more.

A hallmark of Alzheimer’s disease (AD) are the proteinaceous aggregates formed by the amyloid-beta peptide (Aβ) that is deposited inside the brain as amyloid plaques. The accumulation of aggregated Aβ may initiate or enhance pathologic processes in AD. According to the amyloid hypothesis, any agent that has the capability to inhibit Aβ aggregation and/or destroy amyloid plaques represents a potential disease-modifying drug. In 2023, a humanized IgG1 monoclonal antibody (lecanemab) against the Aβ-soluble protofibrils was approved by the US FDA for AD therapy, thus providing compelling support to the amyloid hypothesis. To acquire a deeper insight on the in vivo Aβ aggregation, various animal models, including aged herbivores and carnivores, non-human primates, transgenic rodents, fish and worms were widely exploited. This review is based on the recent data obtained using transgenic animal AD models and presents experimental verification of the critical role in Aβ aggregation seeding of the interactions between zinc ions, Aβ with the isomerized Asp7 (isoD7-Aβ) and the α4β2 nicotinic acetylcholine receptor. Full article

(This article belongs to the Topic Advances in Diagnostics, Brain Delivery Systems and Therapeutics of Neurodegenerative Disease)

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20 pages, 5029 KiB

Open AccessArticle

Integrative Analysis of Machine Learning and Molecule Docking Simulations for Ischemic Stroke Diagnosis and Therapy

by Jingwei Song, Syed Aqib Ali Zaidi, Liangge He, Shuai Zhang and Guangqian Zhou

Molecules 2023, 28(23), 7704; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28237704 - 22 Nov 2023

Viewed by 1172

Abstract

Due to the narrow therapeutic window and high mortality of ischemic stroke, it is of great significance to investigate its diagnosis and therapy. We employed weighted gene coexpression network analysis (WGCNA) to ascertain gene modules related to stroke and used the maSigPro R [...] Read more.

Due to the narrow therapeutic window and high mortality of ischemic stroke, it is of great significance to investigate its diagnosis and therapy. We employed weighted gene coexpression network analysis (WGCNA) to ascertain gene modules related to stroke and used the maSigPro R package to seek the time-dependent genes in the progression of stroke. Three machine learning algorithms were further employed to identify the feature genes of stroke. A nomogram model was built and applied to evaluate the stroke patients. We analyzed single-cell RNA sequencing (scRNA-seq) data to discern microglia subclusters in ischemic stroke. The RNA velocity, pseudo time, and gene set enrichment analysis (GSEA) were performed to investigate the relationship of microglia subclusters. Connectivity map (CMap) analysis and molecule docking were used to screen a therapeutic agent for stroke. A nomogram model based on the feature genes showed a clinical net benefit and enabled an accurate evaluation of stroke patients. The RNA velocity and pseudo time analysis showed that microglia subcluster 0 would develop toward subcluster 2 within 24 h from stroke onset. The GSEA showed that the function of microglia subcluster 0 was opposite to that of subcluster 2. AZ_628, which screened from CMap analysis, was found to have lower binding energy with Mmp12, Lgals3, Fam20c, Capg, Pkm2, Sdc4, and Itga5 in microglia subcluster 2 and maybe a therapeutic agent for the poor development of microglia subcluster 2 after stroke. Our study presents a nomogram model for stroke diagnosis and provides a potential molecule agent for stroke therapy. Full article

(This article belongs to the Topic Advances in Diagnostics, Brain Delivery Systems and Therapeutics of Neurodegenerative Disease)

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18 pages, 2635 KiB

Open AccessArticle

Searching for Metabolic Markers of Stroke in Human Plasma via NMR Analysis

by Nádia Oliveira, Adriana Sousa, Ana Paula Amaral, Gonçalo Graça and Ignacio Verde

Int. J. Mol. Sci. 2023, 24(22), 16173; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms242216173 - 10 Nov 2023

Viewed by 1016

Abstract

More than 12 million people around the world suffer a stroke every year, one every 3 s. Stroke has a variety of causes and is often the result of a complex interaction of risk factors related to age, genetics, gender, lifestyle, and some [...] Read more.

More than 12 million people around the world suffer a stroke every year, one every 3 s. Stroke has a variety of causes and is often the result of a complex interaction of risk factors related to age, genetics, gender, lifestyle, and some cardiovascular and metabolic diseases. Despite this evidence, it is not possible to prevent the onset of stroke. The use of innovative methods for metabolite analysis has been explored in the last years to detect new stroke biomarkers. We use NMR spectroscopy to identify small molecule variations between different stages of stroke risk. The Framingham Stroke Risk Score was used in people over 63 years of age living in long-term care facilities (LTCF) to calculate the probability of suffering a stroke. Using this parameter, three study groups were formed: low stroke risk (LSR, control), moderate stroke risk (MSR) and high stroke risk (HSR). Univariate statistical analysis showed seven metabolites with increasing plasma levels across different stroke risk groups, from LSR to HSR: isoleucine, asparagine, formate, creatinine, dimethylsulfone and two unidentified molecules, which we termed “unknown-1” and “unknown-3”. These metabolic markers can be used for early detection and to detect increasing stages of stroke risk more efficiently. Full article

(This article belongs to the Topic Advances in Diagnostics, Brain Delivery Systems and Therapeutics of Neurodegenerative Disease)

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17 pages, 5642 KiB

Open AccessArticle

PHB2 Alleviates Neurotoxicity of Prion Peptide PrP^106–126 via PINK1/Parkin-Dependent Mitophagy

by Xiaohui Zheng, Kun Liu, Qingqing Xie, Hangkuo Xin, Wei Chen, Shengyu Lin, Danqi Feng and Ting Zhu

Int. J. Mol. Sci. 2023, 24(21), 15919; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms242115919 - 2 Nov 2023

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Abstract

Prion diseases are a group of neurodegenerative diseases characterized by mitochondrial dysfunction and neuronal death. Mitophagy is a selective form of macroautophagy that clears injured mitochondria. Prohibitin 2 (PHB2) has been identified as a novel inner membrane mitophagy receptor that mediates mitophagy. However, [...] Read more.

Prion diseases are a group of neurodegenerative diseases characterized by mitochondrial dysfunction and neuronal death. Mitophagy is a selective form of macroautophagy that clears injured mitochondria. Prohibitin 2 (PHB2) has been identified as a novel inner membrane mitophagy receptor that mediates mitophagy. However, the role of PHB2 in prion diseases remains unclear. In this study, we isolated primary cortical neurons from rats and used the neurotoxic prion peptide PrP^106–126 as a cell model for prion diseases. We examined the role of PHB2 in PrP^106–126-induced mitophagy using Western blotting and immunofluorescence microscopy and assessed the function of PHB2 in PrP^106–126-induced neuronal death using the cell viability assay and the TUNEL assay. The results showed that PrP^106–126 induced mitochondrial morphological abnormalities and mitophagy in primary cortical neurons. PHB2 was found to be indispensable for PrP^106–126-induced mitophagy and was involved in the accumulation of PINK1 and recruitment of Parkin to mitochondria in primary neurons. Additionally, PHB2 depletion exacerbated neuronal cell death induced by PrP^106–126, whereas the overexpression of PHB2 alleviated PrP^106–126 neuronal toxicity. Taken together, this study demonstrated that PHB2 is indispensable for PINK1/Parkin-mediated mitophagy in PrP^106–126-treated neurons and protects neurons against the neurotoxicity of the prion peptide. Full article

(This article belongs to the Topic Advances in Diagnostics, Brain Delivery Systems and Therapeutics of Neurodegenerative Disease)

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13 pages, 2629 KiB

Open AccessArticle

Analysis of Potential Biomarkers in Frontal Temporal Dementia: A Bioinformatics Approach

by Inara Deedar Momin, Jessica Rigler and Kumaraswamy Naidu Chitrala

Int. J. Mol. Sci. 2023, 24(19), 14910; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241914910 - 5 Oct 2023

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Abstract

Frontal temporal dementia (FTD) is a neurological disorder known to have fewer therapeutic options. So far, only a few biomarkers are available for FTD that can be used as potential comorbidity targets. For example, genes such as VCP, which has a role [...] Read more.

Frontal temporal dementia (FTD) is a neurological disorder known to have fewer therapeutic options. So far, only a few biomarkers are available for FTD that can be used as potential comorbidity targets. For example, genes such as VCP, which has a role in breast cancer, and WFS1, which has a role in COVID-19, are known to show a role in FTD as well. To this end, in the present study, we aim to identify potential biomarkers or susceptible genes for FTD that show comorbidities with diseases such as COVID-19 and breast cancer. A dataset from Gene Expression Omnibus containing FTD expression profiles from African American and white ethnicity backgrounds was included in our study. In FTD samples of the GSE193391 dataset, we identified 305 DEGs, with 168 genes being up-regulated and 137 genes being down-regulated. We conducted a comorbidity analysis for COVID-19 and breast cancer, followed by an analysis of potential drug interactions, pathogenicity, analysis of genetic variants, and functional enrichment analysis. Our results showed that the genes AKT3, GFAP, ADCYAP1R1, VDAC1, and C4A have significant transcriptomic alterations in FTD along with the comorbidity status with COVID-19 and breast cancer. Functional pathway analysis revealed that these comorbid genes were significantly enriched in the pathways such as glioma, JAK/STAT signaling, systematic lupus erythematosus, neurodegeneration-multiple diseases, and neuroactive ligand–receptor interaction. Overall, from these results, we concluded that these genes could be recommended as potential therapeutic targets for the treatment of comorbidities (breast cancer and COVID-19) in patients with FTD. Full article

(This article belongs to the Topic Advances in Diagnostics, Brain Delivery Systems and Therapeutics of Neurodegenerative Disease)

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40 pages, 1743 KiB

Open AccessArticle

Chirality Matters: Fine-Tuning of Novel Monoamine Reuptake Inhibitors Selectivity through Manipulation of Stereochemistry

by Predrag Kalaba, Katharina Pacher, Philip John Neill, Vladimir Dragacevic, Martin Zehl, Judith Wackerlig, Michael Kirchhofer, Simone B. Sartori, Hubert Gstach, Shima Kouhnavardi, Anna Fabisikova, Matthias Pillwein, Francisco Monje-Quiroga, Karl Ebner, Alexander Prado-Roller, Nicolas Singewald, Ernst Urban, Thierry Langer, Christian Pifl, Jana Lubec, Johann Jakob Leban and Gert Lubec Show full author list Hide full author list

Biomolecules 2023, 13(9), 1415; https://0-doi-org.brum.beds.ac.uk/10.3390/biom13091415 - 19 Sep 2023

Cited by 1 | Viewed by 1190

Abstract

The high structural similarity, especially in transmembrane regions, of dopamine, norepinephrine, and serotonin transporters, as well as the lack of all crystal structures of human isoforms, make the specific targeting of individual transporters rather challenging. Ligand design itself is also rather limited, as [...] Read more.

The high structural similarity, especially in transmembrane regions, of dopamine, norepinephrine, and serotonin transporters, as well as the lack of all crystal structures of human isoforms, make the specific targeting of individual transporters rather challenging. Ligand design itself is also rather limited, as many chemists, fully aware of the synthetic and analytical challenges, tend to modify lead compounds in a way that reduces the number of chiral centers and hence limits the potential chemical space of synthetic ligands. We have previously shown that increasing molecular complexity by introducing additional chiral centers ultimately leads to more selective and potent dopamine reuptake inhibitors. Herein, we significantly extend our structure-activity relationship of dopamine transporter-selective ligands and further demonstrate how stereoisomers of defined absolute configuration may fine-tune and direct the activity towards distinct targets. From the pool of active compounds, using the examples of stereoisomers 7h and 8h, we further showcase how in vitro activity significantly differs in in vivo drug efficacy experiments, calling for proper validation of individual stereoisomers in animal studies. Furthermore, by generating a large library of compounds with defined absolute configurations, we lay the groundwork for computational chemists to further optimize and rationally design specific monoamine transporter reuptake inhibitors. Full article

(This article belongs to the Topic Advances in Diagnostics, Brain Delivery Systems and Therapeutics of Neurodegenerative Disease)

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15 pages, 991 KiB

Open AccessReview

Blood-Based Biomarkers in the Diagnosis of Chronic Traumatic Encephalopathy: Research to Date and Future Directions

by Michal J. Halicki, Karen Hind and Paul L. Chazot

Int. J. Mol. Sci. 2023, 24(16), 12556; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241612556 - 8 Aug 2023

Viewed by 2014

Abstract

Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disease consistently associated with repetitive traumatic brain injuries (TBIs), which makes multiple professions, such as contact sports athletes and the military, especially susceptible to its onset. There are currently no approved biomarkers to diagnose CTE, thus [...] Read more.

Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disease consistently associated with repetitive traumatic brain injuries (TBIs), which makes multiple professions, such as contact sports athletes and the military, especially susceptible to its onset. There are currently no approved biomarkers to diagnose CTE, thus it can only be confirmed through a post-mortem brain autopsy. Several imaging and cerebrospinal fluid biomarkers have shown promise in the diagnosis. However, blood-based biomarkers can be more easily obtained and quantified, increasing their clinical feasibility and potential for prophylactic use. This article aimed to comprehensively review the studies into potential blood-based biomarkers of CTE, discussing common themes and limitations, as well as suggesting future research directions. While the interest in blood-based biomarkers of CTE has recently increased, the research is still in its early stages. The main issue for many proposed biomarkers is their lack of selectivity for CTE. However, several molecules, such as different phosphorylated tau isoforms, were able to discern CTE from different neurodegenerative diseases. Further, the results from studies on exosomal biomarkers suggest that exosomes are a promising source of biomarkers, reflective of the internal environment of the brain. Nonetheless, more longitudinal studies combining imaging, neurobehavioral, and biochemical approaches are warranted to establish robust biomarkers for CTE. Full article

(This article belongs to the Topic Advances in Diagnostics, Brain Delivery Systems and Therapeutics of Neurodegenerative Disease)

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18 pages, 1726 KiB

Open AccessReview

MicroRNAs-Based Theranostics against Anesthetic-Induced Neurotoxicity

by Roseleena Minz, Praveen Kumar Sharma, Arvind Negi and Kavindra Kumar Kesari

Pharmaceutics 2023, 15(7), 1833; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics15071833 - 27 Jun 2023

Cited by 1 | Viewed by 1256

Abstract

Various clinical reports indicate prolonged exposure to general anesthetic-induced neurotoxicity (in vitro and in vivo). Behavior changes (memory and cognition) are compilations commonly cited with general anesthetics. The ability of miRNAs to modulate gene expression, thereby selectively altering cellular functions, remains one of [...] Read more.

Various clinical reports indicate prolonged exposure to general anesthetic-induced neurotoxicity (in vitro and in vivo). Behavior changes (memory and cognition) are compilations commonly cited with general anesthetics. The ability of miRNAs to modulate gene expression, thereby selectively altering cellular functions, remains one of the emerging techniques in the recent decade. Importantly, engineered miRNAs (which are of the two categories, i.e., agomir and antagomir) to an extent found to mitigate neurotoxicity. Utilizing pre-designed synthetic miRNA oligos would be an ideal analeptic approach for intervention based on indicative parameters. This review demonstrates engineered miRNA’s potential as prophylactics and/or therapeutics minimizing the general anesthetics-induced neurotoxicity. Furthermore, we share our thoughts regarding the current challenges and feasibility of using miRNAs as therapeutic agents to counteract the adverse neurological effects. Moreover, we discuss the scientific status and updates on the novel neuro-miRNAs related to therapy against neurotoxicity induced by amyloid beta (Aβ) and Parkinson’s disease (PD). Full article

(This article belongs to the Topic Advances in Diagnostics, Brain Delivery Systems and Therapeutics of Neurodegenerative Disease)

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