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Open AccessEditorial

Biomarkers in Neurodegenerative Diseases

by Arnab Ghosh

Biomedicines 2022, 10(2), 215; https://doi.org/10.3390/biomedicines10020215 - 20 Jan 2022

Cited by 2 | Viewed by 1554

Abstract

An increasing number of people are affected by various neurodegenerative diseases each year, impacting the quality of life of millions of people worldwide [...] Full article

(This article belongs to the Special Issue Biomarkers in Neurodegenerative Diseases)

Research

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17 pages, 4299 KiB

Open AccessArticle

Quinpirole-Mediated Regulation of Dopamine D2 Receptors Inhibits Glial Cell-Induced Neuroinflammation in Cortex and Striatum after Brain Injury

by Sayed Ibrar Alam, Min Gi Jo, Tae Ju Park, Rahat Ullah, Sareer Ahmad, Shafiq Ur Rehman and Myeong Ok Kim

Biomedicines 2021, 9(1), 47; https://doi.org/10.3390/biomedicines9010047 - 07 Jan 2021

Cited by 18 | Viewed by 2983

Abstract

Brain injury is a significant risk factor for chronic gliosis and neurodegenerative diseases. Currently, no treatment is available for neuroinflammation caused by the action of glial cells following brain injury. In this study, we investigated the quinpirole-mediated activation of dopamine D2 receptors (D2R) [...] Read more.

Brain injury is a significant risk factor for chronic gliosis and neurodegenerative diseases. Currently, no treatment is available for neuroinflammation caused by the action of glial cells following brain injury. In this study, we investigated the quinpirole-mediated activation of dopamine D2 receptors (D2R) in a mouse model of traumatic brain injury (TBI). We also investigated the neuroprotective effects of quinpirole (a D2R agonist) against glial cell-induced neuroinflammation secondary to TBI in adult mice. After the brain injury, we injected quinpirole into the TBI mice at a dose of 1 mg/kg daily intraperitoneally for 7 days. Our results showed suppression of D2R expression and deregulation of downstream signaling molecules in ipsilateral cortex and striatum after TBI on day 7. Quinpirole administration regulated D2R expression and significantly reduced glial cell-induced neuroinflammation via the D2R/Akt/glycogen synthase kinase 3 beta (GSK3-β) signaling pathway after TBI. Quinpirole treatment concomitantly attenuated increase in glial cells, neuronal apoptosis, synaptic dysfunction, and regulated proteins associated with the blood–brain barrier, together with the recovery of lesion volume in the TBI mouse model. Additionally, our in vitro results confirmed that quinpirole reversed the microglial condition media complex-mediated deleterious effects and regulated D2R levels in HT22 cells. This study showed that quinpirole administration after TBI reduced secondary brain injury-induced glial cell activation and neuroinflammation via regulation of the D2R/Akt/GSK3-β signaling pathways. Our study suggests that quinpirole may be a safe therapeutic agent against TBI-induced neurodegeneration. Full article

(This article belongs to the Special Issue Biomarkers in Neurodegenerative Diseases)

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18 pages, 20800 KiB

Open AccessArticle

Somatostatin Ameliorates β-Amyloid-Induced Cytotoxicity via the Regulation of CRMP2 Phosphorylation and Calcium Homeostasis in SH-SY5Y Cells

by Seungil Paik, Rishi K. Somvanshi, Helen A. Oliveira, Shenglong Zou and Ujendra Kumar

Biomedicines 2021, 9(1), 27; https://doi.org/10.3390/biomedicines9010027 - 02 Jan 2021

Cited by 6 | Viewed by 2534

Abstract

Somatostatin is involved in the regulation of multiple signaling pathways and affords neuroprotection in response to neurotoxins. In the present study, we investigated the role of Somatostatin-14 (SST) in cell viability and the regulation of phosphorylation of Collapsin Response Mediator Protein 2 (CRMP2) [...] Read more.

Somatostatin is involved in the regulation of multiple signaling pathways and affords neuroprotection in response to neurotoxins. In the present study, we investigated the role of Somatostatin-14 (SST) in cell viability and the regulation of phosphorylation of Collapsin Response Mediator Protein 2 (CRMP2) (Ser522) via the blockade of Ca²⁺ accumulation, along with the inhibition of cyclin-dependent kinase 5 (CDK5) and Calpain activation in differentiated SH-SY5Y cells. Cell Viability and Caspase 3/7 assays suggest that the presence of SST ameliorates mitochondrial stability and cell survival pathways while augmenting pro-apoptotic pathways activated by Aβ. SST inhibits the phosphorylation of CRMP2 at Ser522 site, which is primarily activated by CDK5. Furthermore, SST effectively regulates Ca²⁺ influx in the presence of Aβ, directly affecting the activity of calpain in differentiated SH-SY5Y cells. We also demonstrated that SSTR2 mediates the protective effects of SST. In conclusion, our results highlight the regulatory role of SST in intracellular Ca²⁺ homeostasis. The neuroprotective role of SST via axonal regeneration and synaptic integrity is corroborated by regulating changes in CRMP2; however, SST-mediated changes in the blockade of Ca²⁺ influx, calpain expression, and toxicity did not correlate with CDK5 expression and p35/25 accumulation. To summarize, our findings suggest two independent mechanisms by which SST mediates neuroprotection and confirms the therapeutic implications of SST in AD as well as in other neurodegenerative diseases where the effective regulation of calcium homeostasis is required for a better prognosis. Full article

(This article belongs to the Special Issue Biomarkers in Neurodegenerative Diseases)

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11 pages, 1751 KiB

Open AccessEditor’s ChoiceArticle

Using Artificial Neural Network to Discriminate Parkinson’s Disease from Other Parkinsonisms by Focusing on Putamen of Dopamine Transporter SPECT Images

by Chung-Yao Chien, Szu-Wei Hsu, Tsung-Lin Lee, Pi-Shan Sung and Chou-Ching Lin

Biomedicines 2021, 9(1), 12; https://doi.org/10.3390/biomedicines9010012 - 24 Dec 2020

Cited by 19 | Viewed by 3515

Abstract

Background: The challenge of differentiating, at an early stage, Parkinson’s disease from parkinsonism caused by other disorders remains unsolved. We proposed using an artificial neural network (ANN) to process images of dopamine transporter single-photon emission computed tomography (DAT-SPECT). Methods: Abnormal DAT-SPECT images of [...] Read more.

Background: The challenge of differentiating, at an early stage, Parkinson’s disease from parkinsonism caused by other disorders remains unsolved. We proposed using an artificial neural network (ANN) to process images of dopamine transporter single-photon emission computed tomography (DAT-SPECT). Methods: Abnormal DAT-SPECT images of subjects with Parkinson’s disease and parkinsonism caused by other disorders were divided into training and test sets. Striatal regions of the images were segmented by using an active contour model and were used as the data to perform transfer learning on a pre-trained ANN to discriminate Parkinson’s disease from parkinsonism caused by other disorders. A support vector machine trained using parameters of semi-quantitative measurements including specific binding ratio and asymmetry index was used for comparison. Results: The predictive accuracy of the ANN classifier (86%) was higher than that of the support vector machine classifier (68%). The sensitivity and specificity of the ANN classifier in predicting Parkinson’s disease were 81.8% and 88.6%, respectively. Conclusions: The ANN classifier outperformed classical biomarkers in differentiating Parkinson’s disease from parkinsonism caused by other disorders. This classifier can be readily included into standalone computer software for clinical application. Full article

(This article belongs to the Special Issue Biomarkers in Neurodegenerative Diseases)

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14 pages, 3663 KiB

Open AccessEditor’s ChoiceArticle

Lupeol, a Plant-Derived Triterpenoid, Protects Mice Brains against Aβ-Induced Oxidative Stress and Neurodegeneration

by Riaz Ahmad, Amjad Khan, Hyeon Jin Lee, Inayat Ur Rehman, Ibrahim Khan, Sayed Ibrar Alam and Myeong Ok Kim

Biomedicines 2020, 8(10), 380; https://doi.org/10.3390/biomedicines8100380 - 26 Sep 2020

Cited by 24 | Viewed by 3646

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that represents 60–70% of all dementia cases. AD is characterized by the formation and accumulation of amyloid-beta (Aβ) plaques, neurofibrillary tangles, and neuronal cell loss. Further accumulation of Aβ in the brain induces oxidative stress, [...] Read more.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that represents 60–70% of all dementia cases. AD is characterized by the formation and accumulation of amyloid-beta (Aβ) plaques, neurofibrillary tangles, and neuronal cell loss. Further accumulation of Aβ in the brain induces oxidative stress, neuroinflammation, and synaptic and memory dysfunction. In this study, we investigated the antioxidant and neuroprotective effects of the natural triterpenoid lupeol in the Aβ_1–42 mouse model of AD. An Intracerebroventricular injection (i.c.v.) of Aβ (3 µL/5 min/mouse) into the brain of a mouse increased the reactive oxygen species (ROS) levels, neuroinflammation, and memory and cognitive dysfunction. The oral administration of lupeol at a dose of 50 mg/kg for two weeks significantly decreased the oxidative stress, neuroinflammation, and memory impairments. Lupeol decreased the oxidative stress via the activation of nuclear factor erythroid 2-related factor-2 (Nrf-2) and heme oxygenase-1 (HO-1) in the brain of adult mice. Moreover, lupeol treatment prevented neuroinflammation by suppressing activated glial cells and inflammatory mediators. Additionally, lupeol treatment significantly decreased the accumulation of Aβ and beta-secretase-1 (BACE-1) expression and enhanced the memory and cognitive function in the Aβ-mouse model of AD. To the best of our knowledge, this is the first study to investigate the anti-oxidative and neuroprotective effects of lupeol against Aβ_1–42-induced neurotoxicity. Our findings suggest that lupeol could serve as a novel, promising, and accessible neuroprotective agent against progressive neurodegenerative diseases such as AD. Full article

(This article belongs to the Special Issue Biomarkers in Neurodegenerative Diseases)

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13 pages, 993 KiB

Open AccessArticle

EDTA Chelation Therapy in the Treatment of Neurodegenerative Diseases: An Update

by Alessandro Fulgenzi, Daniele Vietti and Maria Elena Ferrero

Biomedicines 2020, 8(8), 269; https://doi.org/10.3390/biomedicines8080269 - 03 Aug 2020

Cited by 10 | Viewed by 5516

Abstract

We have previously described the role played by toxic-metal burdens in the etiology of neurodegenerative diseases (ND). We herein report an updated evaluation of toxic-metal burdens in human subjects affected or not affected by ND or other chronic diseases. Each subject underwent a [...] Read more.

We have previously described the role played by toxic-metal burdens in the etiology of neurodegenerative diseases (ND). We herein report an updated evaluation of toxic-metal burdens in human subjects affected or not affected by ND or other chronic diseases. Each subject underwent a chelation test with the chelating agent calcium disodium ethylenediaminetetraacetic acid (CaNA₂EDTA or EDTA) to identify the presence of 20 toxic metals in urine samples using inductively coupled plasma mass spectrometry. Our results show the constant presence of toxic metals, such as lead, cadmium, cesium, and aluminum, in all examined subjects but the absence of beryllium and tellurium. Gadolinium was detected in patients undergoing diagnostic magnetic resonance imaging. The presence of toxic metals was always significantly more elevated in ND patients than in healthy controls. Treatment with EDTA chelation therapy removes toxic-metal burdens and improves patient symptoms. Full article

(This article belongs to the Special Issue Biomarkers in Neurodegenerative Diseases)

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14 pages, 1676 KiB

Open AccessArticle

Monopolar Spindle 1 Kinase (MPS1/TTK) mRNA Expression is Associated with Earlier Development of Clinical Symptoms, Tumor Aggressiveness and Survival of Glioma Patients

by Almuth F. Kessler, Jonas Feldheim, Dominik Schmitt, Julia J. Feldheim, Camelia M. Monoranu, Ralf-Ingo Ernestus, Mario Löhr and Carsten Hagemann

Biomedicines 2020, 8(7), 192; https://doi.org/10.3390/biomedicines8070192 - 03 Jul 2020

Cited by 6 | Viewed by 2227

Abstract

Inhibition of the protein kinase MPS1, a mitotic spindle-checkpoint regulator, reinforces the effects of multiple therapies against glioblastoma multiforme (GBM) in experimental settings. We analyzed MPS1 mRNA-expression in gliomas WHO grade II, III and in clinical subgroups of GBM. Data were obtained by [...] Read more.

Inhibition of the protein kinase MPS1, a mitotic spindle-checkpoint regulator, reinforces the effects of multiple therapies against glioblastoma multiforme (GBM) in experimental settings. We analyzed MPS1 mRNA-expression in gliomas WHO grade II, III and in clinical subgroups of GBM. Data were obtained by qPCR analysis of tumor and healthy brain specimens and correlated with the patients’ clinical data. MPS1 was overexpressed in all gliomas on an mRNA level (ANOVA, p < 0.01) and correlated with tumor aggressiveness. We explain previously published conflicting results on survival: high MPS1 was associated with poorer long term survival when all gliomas were analyzed combined in one group (Cox regression: t < 24 months, p = 0.009, Hazard ratio: 8.0, 95% CI: 1.7–38.4), with poorer survival solely in low-grade gliomas (LogRank: p = 0.02, Cox regression: p = 0.06, Hazard-Ratio: 8.0, 95% CI: 0.9–66.7), but not in GBM (LogRank: p > 0.05). This might be due to their lower tumor volume at the therapy start. GBM patients with high MPS1 mRNA-expression developed clinical symptoms at an earlier stage. This, however, did not benefit their overall survival, most likely due to the more aggressive tumor growth. Since MPS1 mRNA-expression in gliomas was enhanced with increasing tumor aggressiveness, patients with the worst outcome might benefit best from a treatment directed against MPS1. Full article

(This article belongs to the Special Issue Biomarkers in Neurodegenerative Diseases)

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9 pages, 1615 KiB

Open AccessArticle

Unraveling the Role of Inwardly Rectifying Potassium Channels in the Hippocampus of an Aβ_(1–42)-Infused Rat Model of Alzheimer’s Disease

by Enes Akyuz, Chiara Villa, Merve Beker and Birsen Elibol

Biomedicines 2020, 8(3), 58; https://doi.org/10.3390/biomedicines8030058 - 13 Mar 2020

Cited by 8 | Viewed by 2859

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with a complex etiology and characterized by cognitive deficits and memory loss. The pathogenesis of AD is not yet completely elucidated, and no curative treatment is currently available. Inwardly rectifying potassium (Kir) channels are important [...] Read more.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with a complex etiology and characterized by cognitive deficits and memory loss. The pathogenesis of AD is not yet completely elucidated, and no curative treatment is currently available. Inwardly rectifying potassium (Kir) channels are important for playing a key role in maintaining the resting membrane potential and controlling cell excitability, being largely expressed in both excitable and non-excitable tissues, including neurons. Accordingly, the aim of the study is to investigate the role of neuronal Kir channels in AD pathophysiology. The mRNA and protein levels of neuronal Kir2.1, Kir3.1, and Kir6.2 were evaluated by real-time PCR and Western blot analysis from the hippocampus of an amyloid-β(Aβ)_(1-42)-infused rat model of AD. Extracellular deposition of Aβ was confirmed by both histological Congo red staining and immunofluorescence analysis. Significant decreased mRNA and protein levels of Kir2.1 and Kir6.2 channels were observed in the rat model of AD, whereas no differences were found in Kir3.1 channel levels as compared with controls. Our results provide in vivo evidence that Aβ can modulate the expression of these channels, which may represent novel potential therapeutic targets in the treatment of AD. Full article

(This article belongs to the Special Issue Biomarkers in Neurodegenerative Diseases)

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Review

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11 pages, 693 KiB

Open AccessReview

News about the Role of Fluid and Imaging Biomarkers in Neurodegenerative Diseases

by Jacopo Meldolesi

Biomedicines 2021, 9(3), 252; https://doi.org/10.3390/biomedicines9030252 - 04 Mar 2021

Cited by 12 | Viewed by 2743

Abstract

Biomarkers are molecules that are variable in their origin, nature, and mechanism of action; they are of great relevance in biology and also in medicine because of their specific connection with a single or several diseases. Biomarkers are of two types, which in [...] Read more.

Biomarkers are molecules that are variable in their origin, nature, and mechanism of action; they are of great relevance in biology and also in medicine because of their specific connection with a single or several diseases. Biomarkers are of two types, which in some cases are operative with each other. Fluid biomarkers, started around 2000, are generated in fluid from specific proteins/peptides and miRNAs accumulated within two extracellular fluids, either the central spinal fluid or blood plasma. The switch of these proteins/peptides and miRNAs, from free to segregated within extracellular vesicles, has induced certain advantages including higher levels within fluids and lower operative expenses. Imaging biomarkers, started around 2004, are identified in vivo upon their binding by radiolabeled molecules subsequently revealed in the brain by positron emission tomography and/or other imaging techniques. A positive point for the latter approach is the quantitation of results, but expenses are much higher. At present, both types of biomarker are being extensively employed to study Alzheimer’s and other neurodegenerative diseases, investigated from the presymptomatic to mature stages. In conclusion, biomarkers have revolutionized scientific and medical research and practice. Diagnosis, which is often inadequate when based on medical criteria only, has been recently improved by the multiplicity and specificity of biomarkers. Analogous results have been obtained for prognosis. In contrast, improvement of therapy has been limited or fully absent, especially for Alzheimer’s in which progress has been inadequate. An urgent need at hand is therefore the progress of a new drug trial design together with patient management in clinical practice. Full article

(This article belongs to the Special Issue Biomarkers in Neurodegenerative Diseases)

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25 pages, 2565 KiB

Open AccessReview

Relevance of Autophagy and Mitophagy Dynamics and Markers in Neurodegenerative Diseases

by Carlotta Giorgi, Esmaa Bouhamida, Alberto Danese, Maurizio Previati, Paolo Pinton and Simone Patergnani

Biomedicines 2021, 9(2), 149; https://doi.org/10.3390/biomedicines9020149 - 04 Feb 2021

Cited by 32 | Viewed by 4987

Abstract

During the past few decades, considerable efforts have been made to discover and validate new molecular mechanisms and biomarkers of neurodegenerative diseases. Recent discoveries have demonstrated how autophagy and its specialized form mitophagy are extensively associated with the development, maintenance, and progression of [...] Read more.

During the past few decades, considerable efforts have been made to discover and validate new molecular mechanisms and biomarkers of neurodegenerative diseases. Recent discoveries have demonstrated how autophagy and its specialized form mitophagy are extensively associated with the development, maintenance, and progression of several neurodegenerative diseases. These mechanisms play a pivotal role in the homeostasis of neural cells and are responsible for the clearance of intracellular aggregates and misfolded proteins and the turnover of organelles, in particular, mitochondria. In this review, we summarize recent advances describing the importance of autophagy and mitophagy in neurodegenerative diseases, with particular attention given to multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease. We also review how elements involved in autophagy and mitophagy may represent potential biomarkers for these common neurodegenerative diseases. Finally, we examine the possibility that the modulation of autophagic and mitophagic mechanisms may be an innovative strategy for overcoming neurodegenerative conditions. A deeper knowledge of autophagic and mitophagic mechanisms could facilitate diagnosis and prognostication as well as accelerate the development of therapeutic strategies for neurodegenerative diseases. Full article

(This article belongs to the Special Issue Biomarkers in Neurodegenerative Diseases)

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16 pages, 368 KiB

Open AccessReview

NURR1 Alterations in Perinatal Stress: A First Step towards Late-Onset Diseases? A Narrative Review

by Laura Bordoni, Irene Petracci, Jean Calleja-Agius, Joan G. Lalor and Rosita Gabbianelli

Biomedicines 2020, 8(12), 584; https://doi.org/10.3390/biomedicines8120584 - 08 Dec 2020

Cited by 4 | Viewed by 2677

Abstract

Perinatal life represents a delicate phase of development where stimuli of all sorts, coming to or from the mother, can influence the programming of the future baby’s health. These stimuli may have consequences that persist throughout adulthood. Nuclear receptor related 1 protein (NURR1), [...] Read more.

Perinatal life represents a delicate phase of development where stimuli of all sorts, coming to or from the mother, can influence the programming of the future baby’s health. These stimuli may have consequences that persist throughout adulthood. Nuclear receptor related 1 protein (NURR1), a transcription factor with a critical role in the development of the dopaminergic neurons in the midbrain, mediates the response to stressful environmental stimuli in the perinatal period. During pregnancy, low-grade inflammation triggered by maternal obesity, hyperinsulinemia or vaginal infections alters NURR1 expression in human gestational tissues. A similar scenario is triggered by exposure to neurotoxic compounds, which are associated with NURR1 epigenetic deregulation in the offspring, with potential intergenerational effects. Since these alterations have been associated with an increased risk of developing late-onset diseases in children, NURR1, alone, or in combination with other molecular markers, has been proposed as a new prognostic tool and a potential therapeutic target for several pathological conditions. This narrative review describes perinatal stress associated with NURR1 gene deregulation, which is proposed here as a mediator of late-onset consequences of early life events. Full article

(This article belongs to the Special Issue Biomarkers in Neurodegenerative Diseases)

21 pages, 1733 KiB

Open AccessReview

Body Fluid Biomarkers for Alzheimer’s Disease—An Up-To-Date Overview

by Adrian Florian Bălașa, Cristina Chircov and Alexandru Mihai Grumezescu

Biomedicines 2020, 8(10), 421; https://doi.org/10.3390/biomedicines8100421 - 15 Oct 2020

Cited by 44 | Viewed by 4936

Abstract

Neurodegeneration is a highly complex process which is associated with a variety of molecular mechanisms related to ageing. Among neurodegenerative disorders, Alzheimer’s disease (AD) is the most common, affecting more than 45 million individuals. The underlying mechanisms involve amyloid plaques and neurofibrillary tangles [...] Read more.

Neurodegeneration is a highly complex process which is associated with a variety of molecular mechanisms related to ageing. Among neurodegenerative disorders, Alzheimer’s disease (AD) is the most common, affecting more than 45 million individuals. The underlying mechanisms involve amyloid plaques and neurofibrillary tangles (NFTs) deposition, which will subsequently lead to oxidative stress, chronic neuroinflammation, neuron dysfunction, and neurodegeneration. The current diagnosis methods are still limited in regard to the possibility of the accurate and early detection of the diseases. Therefore, research has shifted towards the identification of novel biomarkers and matrices as biomarker sources, beyond amyloid-β and tau protein levels within the cerebrospinal fluid (CSF), that could improve AD diagnosis. In this context, the aim of this paper is to provide an overview of both conventional and novel biomarkers for AD found within body fluids, including CSF, blood, saliva, urine, tears, and olfactory fluids. Full article

(This article belongs to the Special Issue Biomarkers in Neurodegenerative Diseases)

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