Research

18 pages, 6392 KiB

Open AccessArticle

Short-Term Cortical Electrical Stimulation during the Acute Stage of Traumatic Brain Injury Improves Functional Recovery

by Liang-Chao Wang, Wei-Yen Wei and Pei-Chuan Ho

Biomedicines 2022, 10(8), 1965; https://doi.org/10.3390/biomedicines10081965 - 12 Aug 2022

Cited by 4 | Viewed by 1849

Abstract

Functional restoration is an important issue in the treatment of traumatic brain injury (TBI). Various electrical stimulation devices and protocols have been applied in preclinical studies and have shown therapeutic potential for brain trauma. Short-term invasive cortical electrical stimulation during the acute stage [...] Read more.

Functional restoration is an important issue in the treatment of traumatic brain injury (TBI). Various electrical stimulation devices and protocols have been applied in preclinical studies and have shown therapeutic potential for brain trauma. Short-term invasive cortical electrical stimulation during the acute stage of TBI might be a feasible adjuvant therapy for patients with moderate-to-severe brain injury receiving neurosurgical treatment in the intensive care unit. However, the therapeutic effects of short-term multisession cortical electrical stimulation for brain trauma are not clear. This study explored the therapeutic effects of acute-stage short-term cortical electrical stimulation on TBI. We conducted seven sessions of one-hour cortical electrical stimulation from day 0 to day 6 in rats after brain trauma by controlled cortical impact and then evaluated the functional outcome and histopathological changes. Our data showed that short-term cortical electrical stimulation improved motor coordination, short-term memory, and learning ability and attenuated neurological severity after brain trauma. Lesion volume, apoptosis, and gliosis after brain trauma were reduced, and trauma-induced neurogenesis in the hippocampus for the innate neural reparative response was increased. Our study demonstrated that short-term cortical electrical stimulation applied in the acute stage of traumatic brain injury is a potential adjuvant therapy to improve the recovery of neurological deficits. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatments on Neurodegenerative Diseases)

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15 pages, 3329 KiB

Open AccessArticle

Deletion of Wnt10a Is Implicated in Hippocampal Neurodegeneration in Mice

by Jia-He Zhang, Takashi Tasaki, Manabu Tsukamoto, Ke-Yong Wang, Kin-ya Kubo and Kagaku Azuma

Biomedicines 2022, 10(7), 1500; https://doi.org/10.3390/biomedicines10071500 - 25 Jun 2022

Cited by 4 | Viewed by 1793

Abstract

The hippocampus plays an important role in maintaining normal cognitive function and is closely associated with the neuropathogenesis of dementia. Wnt signaling is relevant to neuronal development and maturation, synaptic formation, and plasticity. The role of Wnt10a in hippocampus-associated cognition, however, is largely [...] Read more.

The hippocampus plays an important role in maintaining normal cognitive function and is closely associated with the neuropathogenesis of dementia. Wnt signaling is relevant to neuronal development and maturation, synaptic formation, and plasticity. The role of Wnt10a in hippocampus-associated cognition, however, is largely unclear. Here, we examined the morphological and functional alterations in the hippocampus of Wnt10a-knockout (Wnt10a^-/-) mice. Neurobehavioral tests revealed that Wnt10a^-/- mice exhibited spatial memory impairment and anxiety-like behavior. Immunostaining and Western blot findings showed that the protein expressions of β-catenin, brain-derived neurotrophic factor, and doublecortin were significantly decreased and that the number of activated microglia increased, accompanied by amyloid-β accumulation, synaptic dysfunction, and microglia-associated neuroinflammation in the hippocampi of Wnt10a^-/- mice. Our findings revealed that the deletion of Wnt10a decreased neurogenesis, impaired synaptic function, and induced hippocampal neuroinflammation, eventually leading to hippocampal neurodegeneration and memory deficit, possibly through the β-catenin signaling pathway, providing a novel insight into preventive approaches for hippocampus-dependent cognitive impairment. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatments on Neurodegenerative Diseases)

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20 pages, 2321 KiB

Open AccessArticle

Role of Polyphenol-Derived Phenolic Acid in Mitigation of Inflammasome-Mediated Anxiety and Depression

by Ruth Iban-Arias, Maria Sebastian-Valverde, Henry Wu, Weiting Lyu, Qingli Wu, Jim Simon and Giulio Maria Pasinetti

Biomedicines 2022, 10(6), 1264; https://doi.org/10.3390/biomedicines10061264 - 28 May 2022

Cited by 5 | Viewed by 3778

Abstract

Overexposure to mental stress throughout life is a significant risk factor for the development of neuropsychiatric disorders, including depression and anxiety. The immune system can initiate a physiological response, releasing stress hormones and pro-inflammatory cytokines, in response to stressors. These effects can overcome [...] Read more.

Overexposure to mental stress throughout life is a significant risk factor for the development of neuropsychiatric disorders, including depression and anxiety. The immune system can initiate a physiological response, releasing stress hormones and pro-inflammatory cytokines, in response to stressors. These effects can overcome allostatic physiological mechanisms and generate a pro-inflammatory environment with deleterious effects if occurring chronically. Previous studies in our lab have identified key anti-inflammatory properties of a bioavailable polyphenolic preparation BDPP and its ability to mitigate stress responses via the attenuation of NLRP3 inflammasome-dependent responses. Inflammasome activation is part of the first line of defense against stimuli of different natures, provides a rapid response, and, therefore, is of capital importance within the innate immunity response. malvidin-3-O-glucoside (MG), a natural anthocyanin present in high proportions in grapes, has been reported to exhibit anti-inflammatory effects, but its mechanisms remain poorly understood. This study aims to elucidate the therapeutic potential of MG on inflammasome-induced inflammation in vitro and in a mouse model of chronic unpredictable stress (CUS). Here, it is shown that MG is an anti-pyroptotic phenolic metabolite that targets NLRP3, NLRC4, and AIM2 inflammasomes, subsequently reducing caspase-1 and IL-1β protein levels in murine primary cortical microglia and the brain, as its beneficial effect to counteract anxiety and depression is also demonstrated. The present study supports the role of MG to mitigate bacterial-mediated inflammation (lipopolysaccharide or LPS) in vitro and CUS-induced behavior impairment in vivo to address stress-induced inflammasome-mediated innate response. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatments on Neurodegenerative Diseases)

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18 pages, 7300 KiB

Open AccessArticle

C9orf72 Hexanucleotide Repeat Expansion-Related Neuropathology Is Attenuated by Nasal Rifampicin in Mice

by Yukari Hatanaka, Tomohiro Umeda, Keiko Shigemori, Toshihide Takeuchi, Yoshitaka Nagai and Takami Tomiyama

Biomedicines 2022, 10(5), 1080; https://doi.org/10.3390/biomedicines10051080 - 06 May 2022

Cited by 2 | Viewed by 3384

Abstract

The non-coding GGGGCC hexanucleotide repeat expansion (HRE) in C9orf72 gene is a dominant cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). This intronic mutation elicits the formation of nuclear and cytoplasmic inclusions containing RNA, RNA-binding proteins, and HRE-derived dipeptide repeat proteins [...] Read more.

The non-coding GGGGCC hexanucleotide repeat expansion (HRE) in C9orf72 gene is a dominant cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). This intronic mutation elicits the formation of nuclear and cytoplasmic inclusions containing RNA, RNA-binding proteins, and HRE-derived dipeptide repeat proteins (DPRs), leading to neurodegeneration via the gain-of-toxic function or loss-of-function of relevant proteins. Using C9-500 mice harboring ~500 repeats of the GGGGCC sequence in human C9orf72 gene, we investigated the effects of rifampicin against HRE-related pathological phenotypes. Rifampicin was administered intranasally to 4.5- to 5-month-old mice for 1 month, and their cognitive function and neuropathology were assessed by the Morris water maze test and immunohistochemical staining. Rifampicin treatment reduced the formation of RNA foci and cytoplasmic inclusions containing DPRs or phosphorylated TDP-43, and furthermore, the levels of phosphorylated double-strand RNA-dependent protein kinase (PKR) that regulates repeat-associated non-ATG (RAN) translation. Synapse loss in the hippocampus and neuronal loss and microglial activation in the prefrontal and motor cortices were also attenuated, and mouse memory was significantly improved. Our findings suggest a therapeutic potential of nasal rifampicin in the prevention of C9orf72-linked neurodegenerative disorders. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatments on Neurodegenerative Diseases)

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11 pages, 2568 KiB

Open AccessArticle

Blockade on Lin28a Prevents Cognitive Impairment and Disruption of the Blood-Brain Barrier Induced by Chronic Cerebral Hypoperfusion

by Jae-Min Lee, Joo Hee Lee and Youn-Jung Kim

Biomedicines 2022, 10(4), 852; https://doi.org/10.3390/biomedicines10040852 - 05 Apr 2022

Cited by 1 | Viewed by 1552

Abstract

Lin28a is an RNA-binding protein involved in the translation and regulation of multiple mRNAs. Lin28a is overexpressed in animal models of brain injury. Similarly, our preliminary study found increased Lin28a expression levels in the animal models four to seven days after chronic cerebral [...] Read more.

Lin28a is an RNA-binding protein involved in the translation and regulation of multiple mRNAs. Lin28a is overexpressed in animal models of brain injury. Similarly, our preliminary study found increased Lin28a expression levels in the animal models four to seven days after chronic cerebral hypoperfusion. Therefore, this current study aimed to evaluate the effects of modulating Lin28a on cognition and brain functions. Vascular dementia (VaD) was induced in 12-week-old male Wistar rats using permanent bilateral common carotid artery occlusion (BCCAO), and these rats were treated with Lin28a siRNA on the fourth and seventh day after BCCAO. From the 42nd day after BCCAO, cognitive behavioral experiments were performed for two weeks. VaD induced by BCCAO resulted in cognitive impairment and microglial activation. Lin28a expression was upregulated after BCCAO. Lin28a siRNA treatment alleviated cognitive impairment and overexpression of GFAP and Iba-1 in the brain. Furthermore, the treatment ameliorated the VaD-induced damage to the blood-brain barrier (BBB) components, including PECAM-1, PDGFRβ, occludin, claudin-9, and ZO-1. CCR6 activation after VaD, associated with BBB disruption, was diminished by treatment with Lin28a siRNA. The treatment inhibited VaD-induced microglial activity and alleviated BBB damage. Thus, blocking Lin28a may alleviate cognitive impairment caused by VaD. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatments on Neurodegenerative Diseases)

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18 pages, 3966 KiB

Open AccessArticle

TDP-43 Pathology and Prionic Behavior in Human Cellular Models of Alzheimer’s Disease Patients

by Eva P. Cuevas, Alberto Rodríguez-Fernández, Valle Palomo, Ana Martínez and Ángeles Martín-Requero

Biomedicines 2022, 10(2), 385; https://doi.org/10.3390/biomedicines10020385 - 05 Feb 2022

Cited by 3 | Viewed by 2760

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder for which there is currently no effective treatment. Despite advances in the molecular pathology of the characteristic histopathological markers of the disease (tau protein and β-amyloid), their translation to the clinic has not provided the expected [...] Read more.

Alzheimer’s disease (AD) is a neurodegenerative disorder for which there is currently no effective treatment. Despite advances in the molecular pathology of the characteristic histopathological markers of the disease (tau protein and β-amyloid), their translation to the clinic has not provided the expected results. Increasing evidences have demonstrated the presence of aggregates of TDP-43 (TAR DNA binding protein 43) in the postmortem brains of patients diagnosed with AD. The present research is focused on of the study of the pathological role of TDP-43 in AD. For this purpose, immortalized lymphocytes samples from patients diagnosed with different severity of sporadic AD were used and the TDP-43 pathology was analyzed against controls, looking for differences in their fragmentation, phosphorylation and cellular location using Western blot and immunocytochemical techniques. The results revealed an increase in TDP-43 fragmentation, as well as increased phosphorylation and aberrant localization of TDP-43 in the cytosolic compartment of lymphocytes of patients diagnosed with severe AD. Moreover, a fragment of approximately 25 KD was found in the extracellular medium of cells derived from severe AD individuals that seem to have prion-like characteristics. We conclude that TDP-43 plays a key role in AD pathogenesis and its cell to cell propagation. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatments on Neurodegenerative Diseases)

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11 pages, 1278 KiB

Open AccessArticle

Structure-Based Analysis of Protein Cluster Size for Super-Resolution Microscopy in the Nervous System

by Chia-En Wong, Yuan-Ping Chu and Kuen-Jer Tsai

Biomedicines 2022, 10(2), 295; https://doi.org/10.3390/biomedicines10020295 - 27 Jan 2022

Cited by 3 | Viewed by 2056

Abstract

To overcome the diffraction limit and resolve target structures in greater detail, far-field super-resolution techniques such as stochastic optical reconstruction microscopy (STORM) have been developed, and different STORM algorithms have been developed to deal with the various problems that arise. In particular, the [...] Read more.

To overcome the diffraction limit and resolve target structures in greater detail, far-field super-resolution techniques such as stochastic optical reconstruction microscopy (STORM) have been developed, and different STORM algorithms have been developed to deal with the various problems that arise. In particular, the effect of the local structure is an important issue. For objects with closely correlated distributions, simple Gaussian-based localization algorithms often used in STORM imaging misinterpret overlapping point spread functions (PSFs) as one, which limits the ability of super-resolution imaging to resolve nanoscale local structures and leads to inaccurate length measurements. The STORM super-resolution images of biological specimens from the cluster-forming proteins in the nervous system were reconstructed for localization-based analysis. Generally, the localization of each fluorophore was determined by two-dimensional Gaussian function fitting. Further, the physical shape of the cluster structure information was incorporated into the size parameter of the localization structure analysis in order to generate structure-based fitting algorithms. In the present study, we proposed a novel, structure-based, super-resolution image analysis method: structure-based analysis (SBA), which combines a structural function and a super-resolution localization algorithm. Using SBA, we estimated the size of fluorescent beads, inclusion proteins, and subtle synaptic structures in both wide-field and STORM images. The results show that SBA has a comparable and often superior performance to the commonly used full width at half maximum (FWHM) parameter. We demonstrated that SBA is able to estimate molecular cluster sizes in far-field super-resolution STORM images, and that SBA was comparable and often superior to FWHM. We also certified that SBA provides size estimations that corroborate previously published electron microscopy data. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatments on Neurodegenerative Diseases)

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15 pages, 1953 KiB

Open AccessArticle

Diagnostic Blood Biomarkers in Alzheimer’s Disease

by Jung Eun Park, Tamil Iniyan Gunasekaran, Yeong Hee Cho, Seong-Min Choi, Min-Kyung Song, Soo Hyun Cho, Jahae Kim, Ho-Chun Song, Kyu Yeong Choi, Jang Jae Lee, Zee-Yong Park, Woo Keun Song, Han-Seong Jeong, Kun Ho Lee, Jung Sup Lee and Byeong C. Kim

Biomedicines 2022, 10(1), 169; https://doi.org/10.3390/biomedicines10010169 - 13 Jan 2022

Cited by 13 | Viewed by 3617

Abstract

Potential biomarkers for Alzheimer’s disease (AD) include amyloid β_1–42 (Aβ_1–42), t-Tau, p-Tau₁₈₁, neurofilament light chain (NFL), and neuroimaging biomarkers. Their combined use is useful for diagnosing and monitoring the progress of AD. Therefore, further development of a combination [...] Read more.

Potential biomarkers for Alzheimer’s disease (AD) include amyloid β_1–42 (Aβ_1–42), t-Tau, p-Tau₁₈₁, neurofilament light chain (NFL), and neuroimaging biomarkers. Their combined use is useful for diagnosing and monitoring the progress of AD. Therefore, further development of a combination of these biomarkers is essential. We investigated whether plasma NFL/Aβ_1–42 can serve as a plasma-based primary screening biomarker reflecting brain neurodegeneration and amyloid pathology in AD for monitoring disease progression and early diagnosis. We measured the NFL and Aβ_1–42 concentrations in the CSF and plasma samples and performed correlation analysis to evaluate the utility of these biomarkers in the early diagnosis and monitoring of AD spectrum disease progression. Pearson’s correlation analysis was used to analyse the associations between the fluid biomarkers and neuroimaging data. The study included 136 participants, classified into five groups: 28 cognitively normal individuals, 23 patients with preclinical AD, 22 amyloid-negative patients with amnestic mild cognitive impairment, 32 patients with prodromal AD, and 31 patients with AD dementia. With disease progression, the NFL concentrations increased and Aβ_1–42 concentrations decreased. The plasma and CSF NFL/Aβ_1–42 were strongly correlated (r = 0.558). Plasma NFL/Aβ_1–42 was strongly correlated with hippocampal volume/intracranial volume (r = 0.409). In early AD, plasma NFL/Aβ_1–42 was associated with higher diagnostic accuracy than the individual biomarkers. Moreover, in preclinical AD, plasma NFL/Aβ_1–42 changed more rapidly than the CSF t-Tau or p-Tau₁₈₁ concentrations. Our findings highlight the utility of plasma NFL/Aβ_1–42 as a non-invasive plasma-based biomarker for early diagnosis and monitoring of AD spectrum disease progression. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatments on Neurodegenerative Diseases)

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17 pages, 5837 KiB

Open AccessArticle

Inhibition of DUSP6 Activates Autophagy and Rescues the Retinal Pigment Epithelium in Sodium Iodate-Induced Retinal Degeneration Models In Vivo and In Vitro

by Hao-Yu Tsai, Henkie Isahwan Ahmad Mulyadi Lai, Zhang-Yuan Chen, Tai-Chi Lin, Winnie Khor, Wen-Chuan Kuo, Jia-Pu Syu, Ping-Hsing Tsai, Yi-Ping Yang, Yueh Chien, Shih-Jen Chen, De-Kuang Hwang, Shih-Hwa Chiou and Shih-Jie Chou

Biomedicines 2022, 10(1), 159; https://doi.org/10.3390/biomedicines10010159 - 12 Jan 2022

Cited by 7 | Viewed by 2394

Abstract

Autophagy plays a protective role in the retinal pigment epithelium (RPE) by eliminating damaged organelles in response to reactive oxygen species (ROS). Dual-specificity protein phosphatase 6 (DUSP6), which belongs to the DUSP subfamily, works as a negative-feedback regulator of the extracellular signal-regulated kinase [...] Read more.

Autophagy plays a protective role in the retinal pigment epithelium (RPE) by eliminating damaged organelles in response to reactive oxygen species (ROS). Dual-specificity protein phosphatase 6 (DUSP6), which belongs to the DUSP subfamily, works as a negative-feedback regulator of the extracellular signal-regulated kinase (ERK) pathway. However, the complex interplay between DUSP6 and autophagy induced by ROS in RPE is yet to be investigated. To investigate the relationship between DUSP6 and autophagy, we exposed the ARPE-19 cell line and C57BL/6N mice to sodium iodate (NaIO₃) as an oxidative stress inducer. Our data showed that the inhibition of DUSP6 activity promotes autophagy flux through the ERK pathway via the upregulation of immunoblotting expression in ARPE-19 cells. Live imaging showed a significant increase in autophagic flux activities, which suggested the restoration autophagy after treatment with the DUSP6 inhibitor. Furthermore, the mouse RPE layer exhibited an irregular structure and abnormal deposits following NaIO₃ injection. The retina layer was recovered after being treated with DUSP6 inhibitor; this suggests that DUSP6 inhibitor can rescue retinal damage by restoring the mouse retina’s autophagy flux. This study suggests that the upregulation of DUSP6 can cause autophagy flux malfunctions in the RPE. The DUSP6 inhibitor can restore autophagy induction, which may serve as a potential therapeutic approach for retinal degeneration disease. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatments on Neurodegenerative Diseases)

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15 pages, 2148 KiB

Open AccessArticle

Sex-Specific Metabolic Pathways Were Associated with Alzheimer’s Disease (AD) Endophenotypes in the European Medical Information Framework for AD Multimodal Biomarker Discovery Cohort

by Jin Xu, Rebecca Green, Min Kim, Jodie Lord, Amera Ebshiana, Sarah Westwood, Alison L. Baird, Alejo J. Nevado-Holgado, Liu Shi, Abdul Hye, Stuart G. Snowden, Isabelle Bos, Stephanie J. B. Vos, Rik Vandenberghe, Charlotte E. Teunissen, Mara Ten Kate, Philip Scheltens, Silvy Gabel, Karen Meersmans, Olivier Blin, Jill Richardson, Ellen Elisa De Roeck, Sebastiaan Engelborghs, Kristel Sleegers, Régis Bordet, Lorena Rami, Petronella Kettunen, Magda Tsolaki, Frans R. J. Verhey, Daniel Alcolea, Alberto Lleó, Gwendoline Peyratout, Mikel Tainta, Peter Johannsen, Yvonne Freund-Levi, Lutz Frölich, Valerija Dobricic, Giovanni B. Frisoni, José Luis Molinuevo, Anders Wallin, Julius Popp, Pablo Martinez-Lage, Lars Bertram, Kaj Blennow, Henrik Zetterberg, Johannes Streffer, Pieter Jelle Visser, Simon Lovestone, Petroula Proitsi, Cristina Legido-Quigley and on behalf of the European Medical Information Framework Consortium Show full author list Hide full author list

Biomedicines 2021, 9(11), 1610; https://doi.org/10.3390/biomedicines9111610 - 03 Nov 2021

Cited by 6 | Viewed by 4031

Abstract

Background: physiological differences between males and females could contribute to the development of Alzheimer’s Disease (AD). Here, we examined metabolic pathways that may lead to precision medicine initiatives. Methods: We explored whether sex modifies the association of 540 plasma metabolites with AD endophenotypes [...] Read more.

Background: physiological differences between males and females could contribute to the development of Alzheimer’s Disease (AD). Here, we examined metabolic pathways that may lead to precision medicine initiatives. Methods: We explored whether sex modifies the association of 540 plasma metabolites with AD endophenotypes including diagnosis, cerebrospinal fluid (CSF) biomarkers, brain imaging, and cognition using regression analyses for 695 participants (377 females), followed by sex-specific pathway overrepresentation analyses, APOE ε4 stratification and assessment of metabolites’ discriminatory performance in AD. Results: In females with AD, vanillylmandelate (tyrosine pathway) was increased and tryptophan betaine (tryptophan pathway) was decreased. The inclusion of these two metabolites (area under curve (AUC) = 0.83, standard error (SE) = 0.029) to a baseline model (covariates + CSF biomarkers, AUC = 0.92, SE = 0.019) resulted in a significantly higher AUC of 0.96 (SE = 0.012). Kynurenate was decreased in males with AD (AUC = 0.679, SE = 0.046). Conclusions: metabolic sex-specific differences were reported, covering neurotransmission and inflammation pathways with AD endophenotypes. Two metabolites, in pathways related to dopamine and serotonin, were associated to females, paving the way to personalised treatment. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatments on Neurodegenerative Diseases)

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Review

Jump to: Research, Other

14 pages, 8510 KiB

Open AccessReview

The Role of Glymphatic System in Alzheimer’s and Parkinson’s Disease Pathogenesis

by Francesca R. Buccellato, Marianna D’Anca, Maria Serpente, Andrea Arighi and Daniela Galimberti

Biomedicines 2022, 10(9), 2261; https://doi.org/10.3390/biomedicines10092261 - 13 Sep 2022

Cited by 25 | Viewed by 5219

Abstract

Alzheimer’s disease (AD) is the most common cause of neurodegenerative dementia, whilst Parkinson’s disease (PD) is a neurodegenerative movement disorder. These two neurodegenerative disorders share the accumulation of toxic proteins as a pathological hallmark. The lack of definitive disease-modifying treatments for these neurogenerative [...] Read more.

Alzheimer’s disease (AD) is the most common cause of neurodegenerative dementia, whilst Parkinson’s disease (PD) is a neurodegenerative movement disorder. These two neurodegenerative disorders share the accumulation of toxic proteins as a pathological hallmark. The lack of definitive disease-modifying treatments for these neurogenerative diseases has led to the hypothesis of new pathogenic mechanisms to target and design new potential therapeutic approaches. The recent observation that the glymphatic system is supposed to be responsible for the movement of cerebrospinal fluid into the brain and clearance of metabolic waste has led to study its involvement in the pathogenesis of these classic proteinopathies. Aquaporin-4 (AQP4), a water channel located in the endfeet of astrocyte membrane, is considered a primary driver of the glymphatic clearance system, and defective AQP4-mediated glymphatic drainage has been linked to proteinopathies. The objective of the present review is to present the recent body of knowledge that links the glymphatic system to the pathogenesis of AD and PD disease and other lifestyle factors such as sleep deprivation and exercise that may influence glymphatic system function. We will also focus on the potential neuroimaging approaches that could identify a neuroimaging marker to detect glymphatic system changes. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatments on Neurodegenerative Diseases)

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18 pages, 744 KiB

Open AccessReview

MicroRNAs in Learning and Memory and Their Impact on Alzheimer’s Disease

by I-Fang Wang, Pei-Chuan Ho and Kuen-Jer Tsai

Biomedicines 2022, 10(8), 1856; https://doi.org/10.3390/biomedicines10081856 - 01 Aug 2022

Cited by 10 | Viewed by 2366

Abstract

Learning and memory formation rely on the precise spatiotemporal regulation of gene expression, such as microRNA (miRNA)-associated silencing, to fine-tune gene expression for the induction and maintenance of synaptic plasticity. Much progress has been made in presenting direct evidence of miRNA regulation in [...] Read more.

Learning and memory formation rely on the precise spatiotemporal regulation of gene expression, such as microRNA (miRNA)-associated silencing, to fine-tune gene expression for the induction and maintenance of synaptic plasticity. Much progress has been made in presenting direct evidence of miRNA regulation in learning and memory. Here, we summarize studies that have manipulated miRNA expression using various approaches in rodents, with changes in cognitive performance. Some of these are involved in well-known mechanisms, such as the CREB-dependent signaling pathway, and some of their roles are in fear- and stress-related disorders, particularly cognitive impairment. We also summarize extensive studies on miRNAs correlated with pathogenic tau and amyloid-β that drive the processes of Alzheimer’s disease (AD). Although altered miRNA profiles in human patients with AD and in mouse models have been well studied, little is known about their clinical applications and therapeutics. Studies on miRNAs as biomarkers still show inconsistencies, and more challenges need to be confronted in standardizing blood-based biomarkers for use in AD. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatments on Neurodegenerative Diseases)

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18 pages, 2812 KiB

Open AccessReview

Autophagy Modulation in Aggresome Formation: Emerging Implications and Treatments of Alzheimer’s Disease

by Md. Ataur Rahman, MD. Hasanur Rahman, A. N. M. Mamun-Or-Rashid, Hongik Hwang, Sooyoung Chung, Bonglee Kim and Hyewhon Rhim

Biomedicines 2022, 10(5), 1027; https://doi.org/10.3390/biomedicines10051027 - 29 Apr 2022

Cited by 12 | Viewed by 3791

Abstract

Alzheimer’s disease (AD) is one of the most prevailing neurodegenerative diseases in the world, which is characterized by memory dysfunction and the formation of tau and amyloid β (Aβ) aggregates in multiple brain regions, including the hippocampus and cortex. The formation of senile [...] Read more.

Alzheimer’s disease (AD) is one of the most prevailing neurodegenerative diseases in the world, which is characterized by memory dysfunction and the formation of tau and amyloid β (Aβ) aggregates in multiple brain regions, including the hippocampus and cortex. The formation of senile plaques involving tau hyperphosphorylation, fibrillar Aβ, and neurofibrillary tangles (NFTs) is used as a pathological marker of AD and eventually produces aggregation or misfolded protein. Importantly, it has been found that the failure to degrade these aggregate-prone proteins leads to pathological consequences, such as synaptic impairment, cytotoxicity, neuronal atrophy, and memory deficits associated with AD. Recently, increasing evidence has suggested that the autophagy pathway plays a role as a central cellular protection system to prevent the toxicity induced by aggregation or misfolded proteins. Moreover, it has also been revealed that AD-related protein aggresomes could be selectively degraded by autophagosome and lysosomal fusion through the autophagy pathway, which is known as aggrephagy. Therefore, the regulation of autophagy serve as a useful approach to modulate the formation of aggresomes associated with AD. This review focuses on the recent improvements in the application of natural compounds and small molecules as a potential therapeutic approach for AD prevention and treatment via aggrephagy. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatments on Neurodegenerative Diseases)

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16 pages, 946 KiB

Open AccessReview

Common Shared Pathogenic Aspects of Small Vessels in Heart and Brain Disease

by Rita Moretti, Milijana Janjusevic, Alessandra Lucia Fluca, Riccardo Saro, Giulia Gagno, Alessandro Pierri, Laura Padoan, Luca Restivo, Agnese Derin, Antonio Paolo Beltrami, Paola Caruso, Gianfranco Sinagra and Aneta Aleksova

Biomedicines 2022, 10(5), 1009; https://doi.org/10.3390/biomedicines10051009 - 27 Apr 2022

Cited by 5 | Viewed by 4292

Abstract

Small-vessel disease (SVD), also known as microvascular endothelial dysfunction, is a disorder with negative consequences for various organs such as the heart and brain. Impaired dilatation and constriction of small vessels in the heart lead to reduced blood flow and ischemia independently of [...] Read more.

Small-vessel disease (SVD), also known as microvascular endothelial dysfunction, is a disorder with negative consequences for various organs such as the heart and brain. Impaired dilatation and constriction of small vessels in the heart lead to reduced blood flow and ischemia independently of coronary artery disease (CAD) and are associated with major cardiac events. SVD is usually a silent form of subcortical vascular burden in the brain with various clinical manifestations, such as silent-lacunar-ischemic events and confluent white-matter hyperintensities. Imaging techniques are the main help for clinicians to diagnose cardiac and brain SVD correctly. Markers of inflammation, such as C-reactive protein, tumor-necrosis-factor α, and interleukin 6, provide insight into the disease and markers that negatively influence nitric-oxide bioavailability and promote oxidative stress. Unfortunately, the therapeutic approach against SVD is still not well-defined. In the last decades, various antioxidants, oxidative stress inhibitors, and superoxide scavengers have been the target of extensive investigations due to their potential therapeutic effect, but with unsatisfactory results. In clinical practice, traditional anti-ischemic and risk-reduction therapies for CAD are currently in use for SVD treatment. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatments on Neurodegenerative Diseases)

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22 pages, 873 KiB

Open AccessReview

Adeno-Associated Viral Vectors as Versatile Tools for Neurological Disorders: Focus on Delivery Routes and Therapeutic Perspectives

by Ana Fajardo-Serrano, Alberto J. Rico, Elvira Roda, Adriana Honrubia, Sandra Arrieta, Goiaz Ariznabarreta, Julia Chocarro, Elena Lorenzo-Ramos, Alvaro Pejenaute, Alfonso Vázquez and José Luis Lanciego

Biomedicines 2022, 10(4), 746; https://doi.org/10.3390/biomedicines10040746 - 23 Mar 2022

Cited by 5 | Viewed by 3763

Abstract

It is without doubt that the gene therapy field is currently in the spotlight for the development of new therapeutics targeting unmet medical needs. Thus, considering the gene therapy scenario, neurological diseases in general and neurodegenerative disorders in particular are emerging as the [...] Read more.

It is without doubt that the gene therapy field is currently in the spotlight for the development of new therapeutics targeting unmet medical needs. Thus, considering the gene therapy scenario, neurological diseases in general and neurodegenerative disorders in particular are emerging as the most appealing choices for new therapeutic arrivals intended to slow down, stop, or even revert the natural progressive course that characterizes most of these devastating neurodegenerative processes. Since an extensive coverage of all available literature is not feasible in practical terms, here emphasis was made in providing some advice to beginners in the field with a narrow focus on elucidating the best delivery route available for fulfilling any given AAV-based therapeutic approach. Furthermore, it is worth nothing that the number of ongoing clinical trials is increasing at a breath-taking speed. Accordingly, a landscape view of preclinical and clinical initiatives is also provided here in an attempt to best illustrate what is ongoing in this quickly expanding field. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatments on Neurodegenerative Diseases)

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23 pages, 946 KiB

Open AccessReview

Addressing Blood–Brain Barrier Impairment in Alzheimer’s Disease

by Chanchal Sharma, Hanwoong Woo and Sang Ryong Kim

Biomedicines 2022, 10(4), 742; https://doi.org/10.3390/biomedicines10040742 - 22 Mar 2022

Cited by 24 | Viewed by 4092

Abstract

The blood–brain barrier (BBB) plays a vital role in maintaining the specialized microenvironment of the brain tissue. It facilitates communication while separating the peripheral circulation system from the brain parenchyma. However, normal aging and neurodegenerative diseases can alter and damage the physiological properties [...] Read more.

The blood–brain barrier (BBB) plays a vital role in maintaining the specialized microenvironment of the brain tissue. It facilitates communication while separating the peripheral circulation system from the brain parenchyma. However, normal aging and neurodegenerative diseases can alter and damage the physiological properties of the BBB. In this review, we first briefly present the essential pathways maintaining and regulating BBB integrity, and further review the mechanisms of BBB breakdown associated with normal aging and peripheral inflammation-causing neurodegeneration and cognitive impairments. We also discuss how BBB disruption can cause or contribute to Alzheimer’s disease (AD), the most common form of dementia and a devastating neurological disorder. Next, we document overlaps between AD and vascular dementia (VaD) and briefly sum up the techniques for identifying biomarkers linked to BBB deterioration. Finally, we conclude that BBB breakdown could be used as a biomarker to help diagnose cognitive impairment associated with normal aging and neurodegenerative diseases such as AD. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatments on Neurodegenerative Diseases)

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40 pages, 1213 KiB

Open AccessEditor’s ChoiceReview

Emerging Therapeutic Strategies for Parkinson’s Disease and Future Prospects: A 2021 Update

by Noha A. Gouda, Ahmed Elkamhawy and Jungsook Cho

Biomedicines 2022, 10(2), 371; https://doi.org/10.3390/biomedicines10020371 - 03 Feb 2022

Cited by 29 | Viewed by 6656

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder pathologically distinguished by degeneration of dopaminergic neurons in the substantia nigra pars compacta. Muscle rigidity, tremor, and bradykinesia are all clinical motor hallmarks of PD. Several pathways have been implicated in PD etiology, including mitochondrial dysfunction, [...] Read more.

Parkinson’s disease (PD) is a neurodegenerative disorder pathologically distinguished by degeneration of dopaminergic neurons in the substantia nigra pars compacta. Muscle rigidity, tremor, and bradykinesia are all clinical motor hallmarks of PD. Several pathways have been implicated in PD etiology, including mitochondrial dysfunction, impaired protein clearance, and neuroinflammation, but how these factors interact remains incompletely understood. Although many breakthroughs in PD therapy have been accomplished, there is currently no cure for PD, only trials to alleviate the related motor symptoms. To reduce or stop the clinical progression and mobility impairment, a disease-modifying approach that can directly target the etiology rather than offering symptomatic alleviation remains a major unmet clinical need in the management of PD. In this review, we briefly introduce current treatments and pathophysiology of PD. In addition, we address the novel innovative therapeutic targets for PD therapy, including α-synuclein, autophagy, neurodegeneration, neuroinflammation, and others. Several immunomodulatory approaches and stem cell research currently in clinical trials with PD patients are also discussed. Moreover, preclinical studies and clinical trials evaluating the efficacy of novel and repurposed therapeutic agents and their pragmatic applications with encouraging outcomes are summarized. Finally, molecular biomarkers under active investigation are presented as potentially valuable tools for early PD diagnosis. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatments on Neurodegenerative Diseases)

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15 pages, 1231 KiB

Open AccessReview

Complement and Coagulation System Crosstalk in Synaptic and Neural Conduction in the Central and Peripheral Nervous Systems

by Shani Berkowitz, Joab Chapman, Amir Dori, Shany Guly Gofrit, Nicola Maggio and Efrat Shavit-Stein

Biomedicines 2021, 9(12), 1950; https://doi.org/10.3390/biomedicines9121950 - 20 Dec 2021

Cited by 10 | Viewed by 3504

Abstract

Complement and coagulation are both key systems that defend the body from harm. They share multiple features and are similarly activated. They each play individual roles in the systemic circulation in physiology and pathophysiology, with significant crosstalk between them. Components from both systems [...] Read more.

Complement and coagulation are both key systems that defend the body from harm. They share multiple features and are similarly activated. They each play individual roles in the systemic circulation in physiology and pathophysiology, with significant crosstalk between them. Components from both systems are mapped to important structures in the central nervous system (CNS) and peripheral nervous system (PNS). Complement and coagulation participate in critical functions in neuronal development and synaptic plasticity. During pathophysiological states, complement and coagulation factors are upregulated and can modulate synaptic transmission and neuronal conduction. This review summarizes the current evidence regarding the roles of the complement system and the coagulation cascade in the CNS and PNS. Possible crosstalk between the two systems regarding neuroinflammatory-related effects on synaptic transmission and neuronal conduction is explored. Novel treatment based on the modulation of crosstalk between complement and coagulation may perhaps help to alleviate neuroinflammatory effects in diseased states of the CNS and PNS. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatments on Neurodegenerative Diseases)

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30 pages, 946 KiB

Open AccessSystematic Review

Parkinson’s Disease and SARS-CoV-2 Infection: Particularities of Molecular and Cellular Mechanisms Regarding Pathogenesis and Treatment

by Aurelian Anghelescu, Gelu Onose, Cristina Popescu, Mihai Băilă, Simona Isabelle Stoica, Ruxandra Postoiu, Elena Brumă, Irina Raluca Petcu, Vlad Ciobanu and Constantin Munteanu

Biomedicines 2022, 10(5), 1000; https://doi.org/10.3390/biomedicines10051000 - 26 Apr 2022

Cited by 5 | Viewed by 2877

Abstract

Accumulating data suggest that chronic neuroinflammation-mediated neurodegeneration is a significant contributing factor for progressive neuronal and glial cell death in age-related neurodegenerative pathology. Furthermore, it could be encountered as long-term consequences in some viral infections, including post-COVID-19 Parkinsonism-related chronic sequelae. The current systematic [...] Read more.

Accumulating data suggest that chronic neuroinflammation-mediated neurodegeneration is a significant contributing factor for progressive neuronal and glial cell death in age-related neurodegenerative pathology. Furthermore, it could be encountered as long-term consequences in some viral infections, including post-COVID-19 Parkinsonism-related chronic sequelae. The current systematic review is focused on a recent question aroused during the pandemic’s successive waves: are there post-SARS-CoV-2 immune-mediated reactions responsible for promoting neurodegeneration? Does the host’s dysregulated immune counter-offensive contribute to the pathogenesis of neurodegenerative diseases, emerging as Parkinson’s disease, in a complex interrelation between genetic and epigenetic risk factors? A synthetic and systematic literature review was accomplished based on the ”Preferred Reporting Items for Systematic Principles Reviews and Meta-Analyses” (PRISMA) methodology, including registration on the specific online platform: International prospective register of systematic reviews—PROSPERO, no. 312183. Initially, 1894 articles were detected. After fulfilling the five steps of the selection methodology, 104 papers were selected for this synthetic review. Documentation was enhanced with a supplementary 47 bibliographic resources identified in the literature within a non-standardized search connected to the subject. As a final step of the PRISMA method, we have fulfilled a Population-Intervention-Comparison-Outcome-Time (PICOT)/Population-Intervention-Comparison-Outcome-Study type (PICOS)—based metanalysis of clinical trials identified as connected to our search, targeting the outcomes of rehabilitative kinesitherapeutic interventions compared to clinical approaches lacking such kind of treatment. Accordingly, we identified 10 clinical trials related to our article. The multi/interdisciplinary conventional therapy of Parkinson’s disease and non-conventional multitarget approach to an integrative treatment was briefly analyzed. This article synthesizes the current findings on the pathogenic interference between the dysregulated complex mechanisms involved in aging, neuroinflammation, and neurodegeneration, focusing on Parkinson’s disease and the acute and chronic repercussions of COVID-19. Time will tell whether COVID-19 neuroinflammatory events could trigger long-term neurodegenerative effects and contribute to the worsening and/or explosion of new cases of PD. The extent of the interrelated neuropathogenic phenomenon remains obscure, so further clinical observations and prospective longitudinal cohort studies are needed. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatments on Neurodegenerative Diseases)

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17 pages, 2734 KiB

Open AccessSystematic Review

Type 2 Diabetes Mellitus as a Risk Factor for Alzheimer’s Disease: Review and Meta-Analysis

by Athanasia Athanasaki, Konstantinos Melanis, Ioanna Tsantzali, Maria Ioanna Stefanou, Sofia Ntymenou, Sotirios G. Paraskevas, Theodosis Kalamatianos, Eleni Boutati, Vaia Lambadiari, Konstantinos I. Voumvourakis, George Stranjalis, Sotirios Giannopoulos, Georgios Tsivgoulis and George P. Paraskevas

Biomedicines 2022, 10(4), 778; https://doi.org/10.3390/biomedicines10040778 - 27 Mar 2022

Cited by 23 | Viewed by 3514

Abstract

Alzheimer’s disease is the most common type of dementia, reaching 60–80% of case totals, and is one of the major global causes of the elderly population’s decline in functionality concerning daily life activities. Epidemiological research has already indicated that, in addition to several [...] Read more.

Alzheimer’s disease is the most common type of dementia, reaching 60–80% of case totals, and is one of the major global causes of the elderly population’s decline in functionality concerning daily life activities. Epidemiological research has already indicated that, in addition to several others metabolic factors, diabetes mellitus type 2 is a risk factor of Alzheimer’s disease. Many molecular pathways have been described, and at the same time, there are clues that suggest the connection between type 2 diabetes mellitus and Alzheimer’s disease, through specific genes, autophagy, and even inflammatory pathways. A systematic review with meta-analysis was conducted, and its main goal was to reveal the multilevel connection between these diseases. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatments on Neurodegenerative Diseases)

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24 pages, 1063 KiB

Open AccessSystematic Review

Shared Molecular Targets in Parkinson’s Disease and Arterial Hypertension: A Systematic Review

by Delia Tulbă, Mioara Avasilichioaiei, Natalia Dima, Laura Crăciun, Paul Bălănescu, Adrian Buzea, Cristian Băicuș and Bogdan Ovidiu Popescu

Biomedicines 2022, 10(3), 653; https://doi.org/10.3390/biomedicines10030653 - 11 Mar 2022

Cited by 3 | Viewed by 2544

Abstract

(1) Background: Parkinson’s disease and arterial hypertension are likely to coexist in the elderly, with possible bidirectional interactions. We aimed to assess the role of antihypertensive agents in PD emergence and/or progression. (2) We performed a systematic search on the PubMed database. Studies [...] Read more.

(1) Background: Parkinson’s disease and arterial hypertension are likely to coexist in the elderly, with possible bidirectional interactions. We aimed to assess the role of antihypertensive agents in PD emergence and/or progression. (2) We performed a systematic search on the PubMed database. Studies enrolling patients with Parkinson’s disease who underwent treatment with drugs pertaining to one of the major antihypertensive drug classes (β-blockers, diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and calcium-channel blockers) prior to or after the diagnosis of parkinsonism were scrutinized. We divided the outcome into two categories: neuroprotective and disease-modifying effect. (3) We included 20 studies in the qualitative synthesis, out of which the majority were observational studies, with only one randomized controlled trial. There are conflicting results regarding the effect of antihypertensive drugs on Parkinson’s disease pathogenesis, mainly because of heterogeneous protocols and population. (4) Conclusions: There is low quality evidence that antihypertensive agents might be potential therapeutic targets in Parkinson’s disease, but this hypothesis needs further testing. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatments on Neurodegenerative Diseases)

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