Zeitschriftenartikel: „Neurodegenerative disease modeling“

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Bolus, Harris, Kassi Crocker, Grace Boekhoff-Falk und Stanislava Chtarbanova. „Modeling Neurodegenerative Disorders in Drosophila melanogaster“. International Journal of Molecular Sciences 21, Nr. 9 (26.04.2020): 3055. http://dx.doi.org/10.3390/ijms21093055.

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Drosophila melanogaster provides a powerful genetic model system in which to investigate the molecular mechanisms underlying neurodegenerative diseases. In this review, we discuss recent progress in Drosophila modeling Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic Lateral Sclerosis (ALS), Huntington’s Disease, Ataxia Telangiectasia, and neurodegeneration related to mitochondrial dysfunction or traumatic brain injury. We close by discussing recent progress using Drosophila models of neural regeneration and how these are likely to provide critical insights into future treatments for neurodegenerative disorders.

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Caldwell, Kim A., Corey W. Willicott und Guy A. Caldwell. „Modeling neurodegeneration in Caenorhabditiselegans“. Disease Models & Mechanisms 13, Nr. 10 (01.10.2020): dmm046110. http://dx.doi.org/10.1242/dmm.046110.

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ABSTRACTThe global burden of neurodegenerative diseases underscores the urgent need for innovative strategies to define new drug targets and disease-modifying factors. The nematode Caenorhabditis elegans has served as the experimental subject for multiple transformative discoveries that have redefined our understanding of biology for ∼60 years. More recently, the considerable attributes of C. elegans have been applied to neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease. Transgenic nematodes with genes encoding normal and disease variants of proteins at the single- or multi-copy level under neuronal-specific promoters limits expression to select neuronal subtypes. The anatomical transparency of C. elegans affords the use of co-expressed fluorescent proteins to follow the progression of neurodegeneration as the animals age. Significantly, a completely defined connectome facilitates detailed understanding of the impact of neurodegeneration on organismal health and offers a unique capacity to accurately link cell death with behavioral dysfunction or phenotypic variation in vivo. Moreover, chemical treatments, as well as forward and reverse genetic screening, hasten the identification of modifiers that alter neurodegeneration. When combined, these chemical-genetic analyses establish critical threshold states to enhance or reduce cellular stress for dissecting associated pathways. Furthermore, C. elegans can rapidly reveal whether lifespan or healthspan factor into neurodegenerative processes. Here, we outline the methodologies employed to investigate neurodegeneration in C. elegans and highlight numerous studies that exemplify its utility as a pre-clinical intermediary to expedite and inform mammalian translational research.

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Li, Jonathan, und Ernest Fraenkel. „Phenotyping Neurodegeneration in Human iPSCs“. Annual Review of Biomedical Data Science 4, Nr. 1 (20.07.2021): 83–100. http://dx.doi.org/10.1146/annurev-biodatasci-092820-025214.

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Induced pluripotent stem cell (iPSC) technology holds promise for modeling neurodegenerative diseases. Traditional approaches for disease modeling using animal and cellular models require knowledge of disease mutations. However, many patients with neurodegenerative diseases do not have a known genetic cause. iPSCs offer a way to generate patient-specific models and study pathways of dysfunction in an in vitro setting in order to understand the causes and subtypes of neurodegeneration. Furthermore, iPSC-based models can be used to search for candidate therapeutics using high-throughput screening. Here we review how iPSC-based models are currently being used to further our understanding of neurodegenerative diseases, as well as discuss their challenges and future directions.

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Lepesant, Jean-Antoine. „The promises of neurodegenerative disease modeling“. Comptes Rendus Biologies 338, Nr. 8-9 (August 2015): 584–92. http://dx.doi.org/10.1016/j.crvi.2015.06.018.

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Louit, Aurélie, Todd Galbraith und François Berthod. „In Vitro 3D Modeling of Neurodegenerative Diseases“. Bioengineering 10, Nr. 1 (10.01.2023): 93. http://dx.doi.org/10.3390/bioengineering10010093.

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The study of neurodegenerative diseases (such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, or amyotrophic lateral sclerosis) is very complex due to the difficulty in investigating the cellular dynamics within nervous tissue. Despite numerous advances in the in vivo study of these diseases, the use of in vitro analyses is proving to be a valuable tool to better understand the mechanisms implicated in these diseases. Although neural cells remain difficult to obtain from patient tissues, access to induced multipotent stem cell production now makes it possible to generate virtually all neural cells involved in these diseases (from neurons to glial cells). Many original 3D culture model approaches are currently being developed (using these different cell types together) to closely mimic degenerative nervous tissue environments. The aim of these approaches is to allow an interaction between glial cells and neurons, which reproduces pathophysiological reality by co-culturing them in structures that recapitulate embryonic development or facilitate axonal migration, local molecule exchange, and myelination (to name a few). This review details the advantages and disadvantages of techniques using scaffolds, spheroids, organoids, 3D bioprinting, microfluidic systems, and organ-on-a-chip strategies to model neurodegenerative diseases.

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Leventoux, Nicolas, Satoru Morimoto, Kent Imaizumi, Yuta Sato, Shinichi Takahashi, Kyoko Mashima, Mitsuru Ishikawa et al. „Human Astrocytes Model Derived from Induced Pluripotent Stem Cells“. Cells 9, Nr. 12 (13.12.2020): 2680. http://dx.doi.org/10.3390/cells9122680.

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Induced pluripotent stem cell (iPSC)-based disease modeling has a great potential for uncovering the mechanisms of pathogenesis, especially in the case of neurodegenerative diseases where disease-susceptible cells can usually not be obtained from patients. So far, the iPSC-based modeling of neurodegenerative diseases has mainly focused on neurons because the protocols for generating astrocytes from iPSCs have not been fully established. The growing evidence of astrocytes’ contribution to neurodegenerative diseases has underscored the lack of iPSC-derived astrocyte models. In the present study, we established a protocol to efficiently generate iPSC-derived astrocytes (iPasts), which were further characterized by RNA and protein expression profiles as well as functional assays. iPasts exhibited calcium dynamics and glutamate uptake activity comparable to human primary astrocytes. Moreover, when co-cultured with neurons, iPasts enhanced neuronal synaptic maturation. Our protocol can be used for modeling astrocyte-related disease phenotypes in vitro and further exploring the contribution of astrocytes to neurodegenerative diseases.

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Li, Bang, Da-Jian He, Xiao-Jiang Li und Xiang-Yu Guo. „Modeling neurodegenerative diseases using non-human primates: advances and challenges“. Ageing and Neurodegenerative Diseases 2, Nr. 3 (2022): 12. http://dx.doi.org/10.20517/and.2022.14.

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Neurodegenerative diseases (NDs), such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), are pathologically characterized by progressive loss of selective populations of neurons in the affected brain regions and clinically manifested by cognitive, motor, and psychological dysfunctions. Since aging is the major risk factor for NDs and the elderly population is expected to expand considerably in the coming decades, the prevalence of NDs will significantly increase, leading to a greater medical burden to society and affected families. Despite extensive research on NDs, no effective therapy is available for NDs, largely due to a lack of complete understanding of the pathogenesis of NDs. Although research on small animal and rodent models has provided tremendous knowledge of molecular mechanisms of disease pathogenesis, few translational successes have been reported in clinical trials. In particular, most genetically modified rodent models are unable to recapitulate striking and overt neurodegeneration seen in the patient brains. Non-human primates (NHPs) are the most relevant laboratory animals to humans, and recent studies using NHP neurodegeneration models have uncovered important pathological features of NDs. Here, we review the unique features of NHPs for modeling NDs and new insights into AD, PD, and ALS gained from animal models, highlight the contribution of gene editing techniques to establishing NHP models, and discuss the challenges of investigating NHP models.

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Trudler, Dorit, Swagata Ghatak und Stuart A. Lipton. „Emerging hiPSC Models for Drug Discovery in Neurodegenerative Diseases“. International Journal of Molecular Sciences 22, Nr. 15 (30.07.2021): 8196. http://dx.doi.org/10.3390/ijms22158196.

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Neurodegenerative diseases affect millions of people worldwide and are characterized by the chronic and progressive deterioration of neural function. Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD), represent a huge social and economic burden due to increasing prevalence in our aging society, severity of symptoms, and lack of effective disease-modifying therapies. This lack of effective treatments is partly due to a lack of reliable models. Modeling neurodegenerative diseases is difficult because of poor access to human samples (restricted in general to postmortem tissue) and limited knowledge of disease mechanisms in a human context. Animal models play an instrumental role in understanding these diseases but fail to comprehensively represent the full extent of disease due to critical differences between humans and other mammals. The advent of human-induced pluripotent stem cell (hiPSC) technology presents an advantageous system that complements animal models of neurodegenerative diseases. Coupled with advances in gene-editing technologies, hiPSC-derived neural cells from patients and healthy donors now allow disease modeling using human samples that can be used for drug discovery.

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Haider, Mohamad, Anjali Chauhan, Sana Tariq, Dharam Pal Pathak, Nadeem Siddiqui, Soni Ali, Faheem Hyder Pottoo und Ruhi Ali. „Application of In silico Methods in the Design of Drugs for Neurodegenerative Diseases“. Current Topics in Medicinal Chemistry 21, Nr. 11 (04.08.2021): 995–1011. http://dx.doi.org/10.2174/1568026621666210521164545.

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Neurodegenerative diseases are complex disorders that cause neuron loss, brain aging and ultimately lead to death. These diseases are difficult to treat because of the complex nature of the nervous system, and the available medicines are unable to heal them effectively. This fact implies the need for novel therapeutics to be designed that are ready to stop or a minimum of retard the neurodegeneration process. These days, Computer-Assisted Drug Design (CADD) approaches are a passage to extend the drug development efficiency and to reduce time and cost because traditional drug discovery is both time-consuming as well as costly. Computational or in silico methods came up with powerful tools in drug design against neurodegenerative diseases. This review presents the approaches and theoretical basis of CADD. Also, the successful applications of various in silico studies, including homology modeling, molecular docking, Quantitative Structure-Activity Relationship (QSAR), Molecular Dynamic (MD), De novo drug design, Pharmacophore-based drug design, Virtual Screening (VS), LIGPLOT Analysis, In silico ADMET and drug safety prediction, for treating neurodegenerative diseases have also been included in this review. Major emphasis is given to Alzheimer’s disease and Parkinson’s disease because these two are the most familiar neurodegenerative diseases.

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Wan, Wenbin, Lan Cao, Bill Kalionis, Shijin Xia und Xiantao Tai. „Applications of Induced Pluripotent Stem Cells in Studying the Neurodegenerative Diseases“. Stem Cells International 2015 (2015): 1–11. http://dx.doi.org/10.1155/2015/382530.

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Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons. Incurable neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) show dramatic rising trends particularly in the advanced age groups. However, the underlying mechanisms are not yet fully elucidated, and to date there are no biomarkers for early detection or effective treatments for the underlying causes of these diseases. Furthermore, due to species variation and differences between animal models (e.g., mouse transgenic and knockout models) of neurodegenerative diseases, substantial debate focuses on whether animal and cell culture disease models can correctly model the condition in human patients. In 2006, Yamanaka of Kyoto University first demonstrated a novel approach for the preparation of induced pluripotent stem cells (iPSCs), which displayed similar pluripotency potential to embryonic stem cells (ESCs). Currently, iPSCs studies are permeating many sectors of disease research. Patient sample-derived iPSCs can be used to construct patient-specific disease models to elucidate the pathogenic mechanisms of disease development and to test new therapeutic strategies. Accordingly, the present review will focus on recent progress in iPSC research in the modeling of neurodegenerative disorders and in the development of novel therapeutic options.

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Chang, Chia-Yu, Hsiao-Chien Ting, Ching-Ann Liu, Hong-Lin Su, Tzyy-Wen Chiou, Horng-Jyh Harn und Shinn-Zong Lin. „Induced Pluripotent Stem Cells“. Cell Transplantation 27, Nr. 11 (12.06.2018): 1588–602. http://dx.doi.org/10.1177/0963689718775406.

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Many neurodegenerative diseases are progressive, complex diseases without clear mechanisms or effective treatments. To study the mechanisms underlying these diseases and to develop treatment strategies, a reliable in vitro modeling system is critical. Induced pluripotent stem cells (iPSCs) have the ability to self-renew and possess the differentiation potential to become any kind of adult cell; thus, they may serve as a powerful material for disease modeling. Indeed, patient cell-derived iPSCs can differentiate into specific cell lineages that display the appropriate disease phenotypes and vulnerabilities. In this review, we highlight neuronal differentiation methods and the current development of iPSC-based neurodegenerative disease modeling tools for mechanism study and drug screening, with a discussion of the challenges and future inspiration for application.

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Nair B J, Bipin, und Akshay Rajendran. „Computer aided drug design using virtual screening and molecular energy calculation of a specific neurodegenerative diseases“. International Journal of Engineering & Technology 7, Nr. 1.9 (01.03.2018): 141. http://dx.doi.org/10.14419/ijet.v7i1.9.9751.

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Computer-aided drug design (CADD) is designing a drug with the help of computational algorithms. Information technology advances to creates the structure of molecules, molecular modeling and calculate the binding energies of the drug to initiate a new medicine against neurodegenerative diseases. In our work, we implemented virtual screening of a drug-protein interaction is selected from drug data bank with potential drug bank inhibitory activity for a specific neurodegenerative disease. Here we analyze technical CADD studies of the neurodegenerative diseases. Finally selecting the best alkaloid for a specific neurodegenerative disease and predicting the efficiency using computation of alkaloid with molecular energy.

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Harris, Alexander R., Patrick McGivern und Lezanne Ooi. „Modeling Emergent Properties in the Brain Using Tissue Models to Investigate Neurodegenerative Disease“. Neuroscientist 26, Nr. 3 (13.09.2019): 224–30. http://dx.doi.org/10.1177/1073858419870446.

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Here we describe emergent properties of the brain and the key challenges associated with modelling them in vitro. Modeling emergent properties of the brain will provide insights into brain function, development, and disease.

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Elsaey, Mohamed A., Kazuhiko Namikawa und Reinhard W. Köster. „Genetic Modeling of the Neurodegenerative Disease Spinocerebellar Ataxia Type 1 in Zebrafish“. International Journal of Molecular Sciences 22, Nr. 14 (08.07.2021): 7351. http://dx.doi.org/10.3390/ijms22147351.

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Dominant spinocerebellar ataxias (SCAs) are progredient neurodegenerative diseases commonly affecting the survival of Purkinje cells (PCs) in the human cerebellum. Spinocerebellar ataxia type 1 (SCA1) is caused by the mutated ataxin1 (Atx1) gene product, in which a polyglutamine stretch encoded by CAG repeats is extended in affected SCA1 patients. As a monogenetic disease with the Atx1-polyQ protein exerting a gain of function, SCA1 can be genetically modelled in animals by cell type-specific overexpression. We have established a transgenic PC-specific SCA1 model in zebrafish coexpressing the fluorescent reporter protein mScarlet together with either human wild type Atx1[30Q] as control or SCA1 patient-derived Atx1[82Q]. SCA1 zebrafish display an age-dependent PC degeneration starting at larval stages around six weeks postfertilization, which continuously progresses during further juvenile and young adult stages. Interestingly, PC degeneration is observed more severely in rostral than in caudal regions of the PC population. Although such a neuropathology resulted in no gross locomotor control deficits, SCA1-fish with advanced PC loss display a reduced exploratory behaviour. In vivo imaging in this SCA1 model may help to better understand such patterned PC death known from PC neurodegeneration diseases, to elucidate disease mechanisms and to provide access to neuroprotective compound characterization in vivo.

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Cao, Lei, Lan Tan, Teng Jiang, Xi-Chen Zhu und Jin-Tai Yu. „Induced Pluripotent Stem Cells for Disease Modeling and Drug Discovery in Neurodegenerative Diseases“. Molecular Neurobiology 52, Nr. 1 (23.08.2014): 244–55. http://dx.doi.org/10.1007/s12035-014-8867-6.

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Cárdenas Torres, Andrés Mauricio, Luis Carlos Ealo Otero, Juliana Uribe Perez und Beatriz Liliana Gomez Gomez. „Using Machine Learning Algorithms for Neurodegenerative Disease Gait Classification“. Ingenierías USBMed 14, Nr. 2 (18.09.2023): 8–14. http://dx.doi.org/10.21500/20275846.6081.

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La detección de los síntomas de las enfermedades neurodegenerativas suele producirse en las últimas fases de la enfermedad, por lo que una detección temprana ayudaría a mejorar la calidad de vida del paciente. La base de datos PhysioNet proporciona información sobre la biomecánica de pacientes con la enfermedad de Parkinson (EP), la esclerosis lateral amiotrófica (ELA) y la enfermedad de Huntington (EH). En este trabajo se utilizan datos espacio-temporales para medir el coste energético y la densidad espectral de potencia en estas patologías. Se utilizan técnicas de c-medias difusas, algoritmo de aprendizaje para el análisis de datos multivariados - LAMDA, y redes neuronales para clasificar datos de marcha de voluntarios con enfermedades neurodegenerativas y un grupo de control. Se entrenaron clasificadores de dos clases: Ctrl+PD, Ctrl+PD y Ctrl+HD. El emparejamiento mejoró el ajuste de LAMDA con un 98,3%, el de la red neuronal con un 97,0% y el de Fuzzy C-means con un 90,2%. El uso potencial de estas técnicas de clasificación permitirá la detección temprana de enfermedades neurodegenerativas, incluyendo nuevos dispositivos que permitan el análisis de la marcha fuera del laboratorio.

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Chan, Anthony. „NEURODEGENERATIVE DISEASES“. Reproduction, Fertility and Development 24, Nr. 1 (2012): 288. http://dx.doi.org/10.1071/rdv24n1ab251.

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In the past few decades, a tremendous amount of effort has been invested in developing gene and cell therapies for inherited genetic diseases such as Huntington's disease (HD). However, progress in their clinical application has been very limited. One of the major barriers is the lack of appropriate animal models that allow precise prediction patterns in human patients. Most of the animal models used for gene and cell therapy study are primarily focused on safety and toxicity evaluation, while therapeutic efficacy cannot be fully addressed because they do not carry the same human diseases. Although mouse models of human diseases are available and have been widely used for the development of new therapies, mice are not good predictors for humans because of the fundamental differences (genome composition, body size, life span and metabolic mechanism) between humans and rodents. Although monkeys are one of the best models for studying pharmacokinetics and overall impact of treatment, they are primarily used for safety and toxicity evaluation. Even HD monkey models, created by chemical induction or focal gene transfer in the brain, develop similar cellular pathology, therapeutic efficacy and systemic evaluation cannot be determined, which is one of the major barriers in drug and therapeutic development. The development of transgenic HD monkeys has opened the door for a new paradigm of animal modeling for the advancement of novel gene and cell therapy. HD monkeys not only carry the genetic defect that leads to human HD, they also develop clinical features comparable to humans that no other animal model does. While testing in HD monkeys has yet to be achieved until a cohort of well characterized HD monkeys was established, iPS cell lines derived from HD monkeys with a board spectrum of HD pathology and clinical features are a unique in vitro model for studying HD pathogenesis and the development of novel therapeutic approaches. New knowledge and treatments generated from iPS cells can next be translated and applied in HD monkeys from whom the stem cells were derived, thus the goal of personalized medicine can also be evaluated. This work was funded by a grant from NCRR/NIH (R24RR018827).

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Bera, Indrani. „Current Therapy and Computational Drug Designing Approaches for Neurodegenerative Diseases -with Focus on Alzheimer’s and Parkinson’s.“ Current Signal Transduction Therapy 14, Nr. 2 (10.10.2019): 122–28. http://dx.doi.org/10.2174/1574362413666180312125419.

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Background: Neurodegenerative diseases are age-related ailments which are characterized by progressive neuronal damage and loss. These diseases can be caused by both genetic and environmental factors. Alzheimer’s and Parkinson’s are the most predominant neurodegenerative diseases. Though various research strategies have been employed to eliminate the cause of the disease, till date successful strategies available are symptomatic. Various compounds have been designed against the targets, such as BACE1, acetylcholinesterase, glycogen synthase kinase, muscarinic acetylcholine receptor etc. Methods: This review consists of information gathered from various research articles and review papers in the concerned field. An attempt was made to identify important findings from these papers. Important in silico techniques used in the identification of drug candidates and newly designed compounds as therapeutics for neurodegenerative diseases were summarized. Results: Sixty papers were included in this review. A comprehensive overview of computer aided drug designing techniques used aimed at the identification of new drug candidates is provided. Ligand based drug design approaches such as QSAR, virtual screening and pharmacophore have been described. Current therapies used against Alzheimer’s and Parkinson’s have summarized. New compounds against the targets of for Alzheimer’s and Parkinson’s identified by computational screening of compounds have been summarized. Conclusion: The findings of this review confirm that therapies and current successful strategies for neurodegenerative disease are mainly symptomatic. Current research is mainly focused on preventing the progress of neurodegeneration. Various in silico techniques; ligand-based methods such as QSAR, virtual screening, pharmacophore mapping and structure-based methods such as homology modeling, docking studies have been used to identify therapeutic compounds for Alzheimer’s and Parkinson’s.

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Okano, Hideyuki, und Satoru Morimoto. „iPSC-based disease modeling and drug discovery in cardinal neurodegenerative disorders“. Cell Stem Cell 29, Nr. 2 (Februar 2022): 189–208. http://dx.doi.org/10.1016/j.stem.2022.01.007.

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Sun, Ming, und Yuanjia Wang. „Nonlinear model with random inflection points for modeling neurodegenerative disease progression“. Statistics in Medicine 37, Nr. 30 (06.09.2018): 4721–42. http://dx.doi.org/10.1002/sim.7951.

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Kumar, Mandeep, Nhung Thi Phuong Nguyen, Marco Milanese und Giambattista Bonanno. „Insights into Human-Induced Pluripotent Stem Cell-Derived Astrocytes in Neurodegenerative Disorders“. Biomolecules 12, Nr. 3 (23.02.2022): 344. http://dx.doi.org/10.3390/biom12030344.

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Most neurodegenerative disorders have complex and still unresolved pathology characterized by progressive neuronal damage and death. Astrocytes, the most-abundant non-neuronal cell population in the central nervous system, play a vital role in these processes. They are involved in various functions in the brain, such as the regulation of synapse formation, neuroinflammation, and lactate and glutamate levels. The development of human-induced pluripotent stem cells (iPSCs) reformed the research in neurodegenerative disorders allowing for the generation of disease-relevant neuronal and non-neuronal cell types that can help in disease modeling, drug screening, and, possibly, cell transplantation strategies. In the last 14 years, the differentiation of human iPSCs into astrocytes allowed for the opportunity to explore the contribution of astrocytes to neurodegenerative diseases. This review discusses the development protocols and applications of human iPSC-derived astrocytes in the most common neurodegenerative conditions.

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Wu, Ying-Chieh, Tuuli-Maria Sonninen, Sanni Peltonen, Jari Koistinaho und Šárka Lehtonen. „Blood–Brain Barrier and Neurodegenerative Diseases—Modeling with iPSC-Derived Brain Cells“. International Journal of Molecular Sciences 22, Nr. 14 (19.07.2021): 7710. http://dx.doi.org/10.3390/ijms22147710.

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The blood–brain barrier (BBB) regulates the delivery of oxygen and important nutrients to the brain through active and passive transport and prevents neurotoxins from entering the brain. It also has a clearance function and removes carbon dioxide and toxic metabolites from the central nervous system (CNS). Several drugs are unable to cross the BBB and enter the CNS, adding complexity to drug screens targeting brain disorders. A well-functioning BBB is essential for maintaining healthy brain tissue, and a malfunction of the BBB, linked to its permeability, results in toxins and immune cells entering the CNS. This impairment is associated with a variety of neurological diseases, including Alzheimer’s disease and Parkinson’s disease. Here, we summarize current knowledge about the BBB in neurodegenerative diseases. Furthermore, we focus on recent progress of using human-induced pluripotent stem cell (iPSC)-derived models to study the BBB. We review the potential of novel stem cell-based platforms in modeling the BBB and address advances and key challenges of using stem cell technology in modeling the human BBB. Finally, we highlight future directions in this area.

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Miccoli, Beatrice, Dries Braeken und Yi-Chen Ethan Li. „Brain-on-a-chip Devices for Drug Screening and Disease Modeling Applications“. Current Pharmaceutical Design 24, Nr. 45 (16.04.2019): 5419–36. http://dx.doi.org/10.2174/1381612825666190220161254.

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:Neurodegenerative disorders are related to the progressive functional loss of the brain, often connected to emotional and physical disability and, ultimately, to death. These disorders, strongly connected to the aging process, are becoming increasingly more relevant due to the increase of life expectancy. Current pharmaceutical treatments poorly tackle these diseases, mainly acting only on their symptomology. One of the main reasons of this is the current drug development process, which is not only expensive and time-consuming but, also, still strongly relies on animal models at the preclinical stage.:Organ-on-a-chip platforms have the potential to strongly impact and improve the drug screening process by recreating in vitro the functionality of human organs. Patient-derived neurons from different regions of the brain can be directly grown and differentiated on a brain-on-a-chip device where the disease development, progression and pharmacological treatments can be studied and monitored in real time. The model reliability is strongly improved by using human-derived cells, more relevant than animal models for pharmacological screening and disease monitoring. The selected cells will be then capable of proliferating and organizing themselves in the in vivo environment thanks to the device architecture, materials selection and bio-chemical functionalization.:In this review, we start by presenting the fundamental strategies adopted for brain-on-a-chip devices fabrication including e.g., photolithography, micromachining and 3D printing technology. Then, we discuss the state-of-theart of brain-on-a-chip platforms including their role in the study of the functional architecture of the brain e.g., blood-brain barrier, or of the most diffuse neurodegenerative diseases like Alzheimer’s and Parkinson’s. At last, the current limitations and future perspectives of this approach for the development of new drugs and neurodegenerative diseases modeling will be discussed.

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Khan, Engila, Ikramul Hasan und M. Emdadul Haque. „Parkinson’s Disease: Exploring Different Animal Model Systems“. International Journal of Molecular Sciences 24, Nr. 10 (22.05.2023): 9088. http://dx.doi.org/10.3390/ijms24109088.

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Disease modeling in non-human subjects is an essential part of any clinical research. To gain proper understanding of the etiology and pathophysiology of any disease, experimental models are required to replicate the disease process. Due to the huge diversity in pathophysiology and prognosis in different diseases, animal modeling is customized and specific accordingly. As in other neurodegenerative diseases, Parkinson’s disease is a progressive disorder coupled with varying forms of physical and mental disabilities. The pathological hallmarks of Parkinson’s disease are associated with the accumulation of misfolded protein called α-synuclein as Lewy body, and degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) area affecting the patient’s motor activity. Extensive research has already been conducted regarding animal modeling of Parkinson’s diseases. These include animal systems with induction of Parkinson’s, either pharmacologically or via genetic manipulation. In this review, we will be summarizing and discussing some of the commonly employed Parkinson’s disease animal model systems and their applications and limitations.

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Najib, Nor H. M., Yong H. Nies, Syarifah A. S. Abd Halim, Mohamad F. Yahaya, Srijit Das, Wei L. Lim und Seong L. Teoh. „Modeling Parkinson’s Disease in Zebrafish“. CNS & Neurological Disorders - Drug Targets 19, Nr. 5 (13.11.2020): 386–99. http://dx.doi.org/10.2174/1871527319666200708124117.

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Parkinson’s Disease (PD) is one of the most common neurodegenerative disorders that affects the motor system, and includes cardinal motor symptoms such as resting tremor, cogwheel rigidity, bradykinesia and postural instability. Its prevalence is increasing worldwide due to the increase in life span. Although, two centuries since the first description of the disease, no proper cure with regard to treatment strategies and control of symptoms could be reached. One of the major challenges faced by the researchers is to have a suitable research model. Rodents are the most common PD models used, but no single model can replicate the true nature of PD. In this review, we aim to discuss another animal model, the zebrafish (Danio rerio), which is gaining popularity. Zebrafish brain has all the major structures found in the mammalian brain, with neurotransmitter systems, and it also possesses a functional blood-brain barrier similar to humans. From the perspective of PD research, the zebrafish possesses the ventral diencephalon, which is thought to be homologous to the mammalian substantia nigra. We summarize the various zebrafish models available to study PD, namely chemical-induced and genetic models. The zebrafish can complement the use of other animal models for the mechanistic study of PD and help in the screening of new potential therapeutic compounds.

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Soufi, W., M. Merad, F. BOUKLI Hacene und S. Ghalem. „Study of Monoamine Oxidase-B and Indole Derivatives Using Two Molecular Docking Programs: Molegro and MOE“. International Journal of Scientific Research and Management 8, Nr. 09 (30.09.2020): 25–31. http://dx.doi.org/10.18535/ijsrm/v8i09.c01.

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Inhibition of the enzyme Monoamine oxidase (MAO) is an important approach in the treatment of Parkinson’s disease. A series of indole derivatives were synthesised and evaluated as inhibitors of MAO-B may give insight to develop new ways of antiparkinson drug, In general, the derivatives were found to be selective MAO-B inhibitors with IC50 values . MAO-B inhibitors, are considered useful in the therapy of Parkinson’s disease since oxidation by MAO-B represents a major catabolic pathway of dopamine in the central nervous system . Our goal of research is to study the inhibition of MAO-B by molecular modeling methods. Different molecular modeling tools are used to perform this work (molecular mechanics, molecular dynamics and molecular docking by two programms MDV ( molegro virtual docker) and MOE (modelling Opering Environment. The results obtained from this work, into which the inhibition of MAO-B by molecular modeling methods was elucidated, allow us to conclude that indole derivatives are promising reversible MAO-B inhibitors with a possible role in the treatment of neurodegenerative diseases such as Parkinson’s disease (PD).

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Lozanska, Bonka, Milena Georgieva, George Miloshev und Charilaos Xenodochidis. „Ageing and Neurodegeneration – The Role of Neurotransmitters’ Activity“. International Journal Bioautomation 26, Nr. 4 (Dezember 2022): 325–38. http://dx.doi.org/10.7546/ijba.2022.26.4.000879.

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Disease and ageing are linked in many ways and especially by the mechanisms they share. For many diseases, the process of ageing is the main culprit leading to the pathology. Hence, it is crucial to understand the process of ageing, and its molecular and cellular mechanisms to have a better understanding and perspective on these age-related diseases. Neurodegenerative diseases are probably the most common types of age-related diseases. Their pathology is complex, however, changes in neurotransmitter levels are almost always present. These types of changes occur during ageing as well, therefore, exploring the link between those processes can give a clue for possible treatments. Monoamine oxidases (MAOs) are enzymes that break down monoamine neurotransmitters and their dysregulation has long been recorded in age-related neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. There is strong evidence that modulating the MAOs’ expression and activity can be beneficial for patients suffering from these illnesses. Herein we critically analyze the literature and make associations among ageing, MAOs’ activity and neurotransmitters’ levels, thus highlighting their role in neurodegenerative diseases.

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Csöbönyeiová, Mária, Štefan Polák und L’uboš Danišovič. „Recent approaches and challenges in iPSCs: modeling and cell-based therapy of Alzheimer’s disease“. Reviews in the Neurosciences 27, Nr. 5 (01.07.2016): 457–64. http://dx.doi.org/10.1515/revneuro-2015-0054.

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AbstractThe lack of effective therapies for different neurodegenerative disorders has placed huge burdens on society. To overcome the restricted capacity of the central nervous system for regeneration, the promising alternative would be to use stem cells for more effective treatment of chronic degenerative and inflammatory neurological conditions and also of acute neuronal damage and from injuries or cerebrovascular diseases. The generation of induced pluripotent stem cells from somatic cells by the ectopic expression of specific transcription factors has provided the regenerative medicine field with a new tool for investigating and treating neurodegenerative diseases, including Alzheimer’s disease (AD). This technology provides an alternative to traditional approaches, such as nuclear transfer and somatic cell fusion using embryonic stem cells. However, due to a problem in standardization of certain reprogramming techniques and systems research, the induced pluripotent stem cell-based technology is still in its infancy. The present paper is aimed at a brief review of the current status in modeling and cell-based therapies for AD.

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Jhala, Shivraj S., und Alan S. Hazell. „Modeling neurodegenerative disease pathophysiology in thiamine deficiency: Consequences of impaired oxidative metabolism“. Neurochemistry International 58, Nr. 3 (Februar 2011): 248–60. http://dx.doi.org/10.1016/j.neuint.2010.11.019.

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Vera, E., und L. Studer. „When rejuvenation is a problem: challenges of modeling late-onset neurodegenerative disease“. Development 142, Nr. 18 (15.09.2015): 3085–89. http://dx.doi.org/10.1242/dev.120667.

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D'Souza, Gary X., Shannon E. Rose, Allison Knupp, Daniel A. Nicholson, Christopher Dirk Keene und Jessica E. Young. „The application of in vitro ‐derived human neurons in neurodegenerative disease modeling“. Journal of Neuroscience Research 99, Nr. 1 (13.03.2020): 124–40. http://dx.doi.org/10.1002/jnr.24615.

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Shastry, Surabhi, Junkai Hu, Mingyao Ying und Xiaobo Mao. „Cell Therapy for Parkinson’s Disease“. Pharmaceutics 15, Nr. 12 (22.11.2023): 2656. http://dx.doi.org/10.3390/pharmaceutics15122656.

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Parkinson’s Disease (PD) is a neurodegenerative disease characterized by the progressive loss of dopaminergic neurons of the substantia nigra pars compacta with a reduction in dopamine concentration in the striatum. It is a substantial loss of dopaminergic neurons that is responsible for the classic triad of PD symptoms, i.e., resting tremor, muscular rigidity, and bradykinesia. Several current therapies for PD may only offer symptomatic relief and do not address the underlying neurodegeneration of PD. The recent developments in cellular reprogramming have enabled the development of previously unachievable cell therapies and patient-specific modeling of PD through Induced Pluripotent Stem Cells (iPSCs). iPSCs possess the inherent capacity for pluripotency, allowing for their directed differentiation into diverse cell lineages, such as dopaminergic neurons, thus offering a promising avenue for addressing the issue of neurodegeneration within the context of PD. This narrative review provides a comprehensive overview of the effects of dopamine on PD patients, illustrates the versatility of iPSCs and their regenerative abilities, and examines the benefits of using iPSC treatment for PD as opposed to current therapeutic measures. In means of providing a treatment approach that reinforces the long-term survival of the transplanted neurons, the review covers three supplementary avenues to reinforce the potential of iPSCs.

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Dolan, Michael-John, Martine Therrien, Saša Jereb, Tushar Kamath, Vahid Gazestani, Trevor Atkeson, Samuel E. Marsh et al. „Exposure of iPSC-derived human microglia to brain substrates enables the generation and manipulation of diverse transcriptional states in vitro“. Nature Immunology 24, Nr. 8 (27.07.2023): 1382–90. http://dx.doi.org/10.1038/s41590-023-01558-2.

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AbstractMicroglia, the macrophages of the brain parenchyma, are key players in neurodegenerative diseases such as Alzheimer’s disease. These cells adopt distinct transcriptional subtypes known as states. Understanding state function, especially in human microglia, has been elusive owing to a lack of tools to model and manipulate these cells. Here, we developed a platform for modeling human microglia transcriptional states in vitro. We found that exposure of human stem-cell-differentiated microglia to synaptosomes, myelin debris, apoptotic neurons or synthetic amyloid-beta fibrils generated transcriptional diversity that mapped to gene signatures identified in human brain microglia, including disease-associated microglia, a state enriched in neurodegenerative diseases. Using a new lentiviral approach, we demonstrated that the transcription factor MITF drives a disease-associated transcriptional signature and a highly phagocytic state. Together, these tools enable the manipulation and functional interrogation of human microglial states in both homeostatic and disease-relevant contexts.

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Hu, Xinchao, Chengyuan Mao, Liyuan Fan, Haiyang Luo, Zhengwei Hu, Shuo Zhang, Zhihua Yang et al. „Modeling Parkinson’s Disease Using Induced Pluripotent Stem Cells“. Stem Cells International 2020 (12.03.2020): 1–15. http://dx.doi.org/10.1155/2020/1061470.

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Parkinson’s disease (PD) is the second most common neurodegenerative disease. The molecular mechanisms of PD at the cellular level involve oxidative stress, mitochondrial dysfunction, autophagy, axonal transport, and neuroinflammation. Induced pluripotent stem cells (iPSCs) with patient-specific genetic background are capable of directed differentiation into dopaminergic neurons. Cell models based on iPSCs are powerful tools for studying the molecular mechanisms of PD. The iPSCs used for PD studies were mainly from patients carrying mutations in synuclein alpha (SNCA), leucine-rich repeat kinase 2 (LRRK2), PTEN-induced putative kinase 1 (PINK1), parkin RBR E3 ubiquitin protein ligase (PARK2), cytoplasmic protein sorting 35 (VPS35), and variants in glucosidase beta acid (GBA). In this review, we summarized the advances in molecular mechanisms of Parkinson’s disease using iPSC models.

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Suzuki, Mari, Kazunori Sango und Yoshitaka Nagai. „Roles of α-Synuclein and Disease-Associated Factors in Drosophila Models of Parkinson’s Disease“. International Journal of Molecular Sciences 23, Nr. 3 (28.01.2022): 1519. http://dx.doi.org/10.3390/ijms23031519.

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α-Synuclein (αSyn) plays a major role in the pathogenesis of Parkinson’s disease (PD), which is the second most common neurodegenerative disease after Alzheimer’s disease. The accumulation of αSyn is a pathological hallmark of PD, and mutations in the SNCA gene encoding αSyn cause familial forms of PD. Moreover, the ectopic expression of αSyn has been demonstrated to mimic several key aspects of PD in experimental model systems. Among the various model systems, Drosophila melanogaster has several advantages for modeling human neurodegenerative diseases. Drosophila has a well-defined nervous system, and numerous tools have been established for its genetic analyses. The rapid generation cycle and short lifespan of Drosophila renders them suitable for high-throughput analyses. PD model flies expressing αSyn have contributed to our understanding of the roles of various disease-associated factors, including genetic and nongenetic factors, in the pathogenesis of PD. In this review, we summarize the molecular pathomechanisms revealed to date using αSyn-expressing Drosophila models of PD, and discuss the possibilities of using these models to demonstrate the biological significance of disease-associated factors.

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Kulikova, O. I., T. N. Fedorova und V. S. Orlova. „MODELING OF PARKINSON’S DISEASE USING ENVIRONMENTAL NEUROTOXINS (REVIEW)“. Toxicological Review, Nr. 2 (28.04.2019): 9–15. http://dx.doi.org/10.36946/0869-7922-2019-2-9-15.

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In recent years, there has been an increase in the prevalence of neurodegenerative diseases including Parkinson’s disease (PD). It is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta, leading to disability of patients and large financial costs of the treatment and rehabilitation. In this regard, the understanding of the environmental factors causing this disease, the development of adequate experimental models for studying its pathogenesis, and the search for strategies to prevent its development, as well as possible neuroprotective drugs, have fundamental scientific value. Although some researchers believe that genetic mutations and aging of the population are the main factors for the development of PD, a lot of studies have shown that PD may be caused by exposure to a number of toxins which enter the body from the environment. This review discusses the main toxic substances that cause the development of PD and, therefore, are used to model this disease in animals and cell cultures, as well as the mechanisms of action of neurotoxins, and the advantages and disadvantages of specific models.

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Kumar, Sunil, Amritha Manoharan, Jayalakshmi J, Mohamed A. Abdelgawad, Wael A. Mahdi, Sultan Alshehri, Mohammed M. Ghoneim et al. „Exploiting butyrylcholinesterase inhibitors through a combined 3-D pharmacophore modeling, QSAR, molecular docking, and molecular dynamics investigation“. RSC Advances 13, Nr. 14 (2023): 9513–29. http://dx.doi.org/10.1039/d3ra00526g.

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Nilsson, Lars-Göran. „Memory Processes, Aging, Cognitive Decline, and Neurodegenerative Diseases“. European Psychologist 11, Nr. 4 (Januar 2006): 304–11. http://dx.doi.org/10.1027/1016-9040.11.4.304.

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This paper presents four domains of markers that have been found to predict later cognitive impairment and neurodegenerative disease. These four domains are (1) data patterns of memory performance, (2) cardiovascular factors, (3) genetic markers, and (4) brain activity. The critical features of each domain are illustrated with data from the longitudinal Betula Study on memory, aging, and health ( Nilsson et al., 1997 ; Nilsson et al., 2004 ). Up to now, early signs regarding these domains have been examined one by one and it has been found that they are associated with later cognitive impairment and neurodegenerative disease. However, it was also found that each marker accounts for only a very small part of the total variance, implying that single markers should not be used as predictors for cognitive decline or neurodegenerative disease. It is discussed whether modeling and simulations should be used as tools to combine markers at different levels to increase the amount of explained variance.

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Xie, Y. Z., und R. X. Zhang. „Neurodegenerative diseases in a dish: the promise of iPSC technology in disease modeling and therapeutic discovery“. Neurological Sciences 36, Nr. 1 (30.10.2014): 21–27. http://dx.doi.org/10.1007/s10072-014-1989-9.

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Muñoz, Sonia Sanz, Martin Engel, Rachelle Balez, Dzung Do-Ha, Mauricio Castro Cabral-da-Silva, Damian Hernández, Tracey Berg et al. „A Simple Differentiation Protocol for Generation of Induced Pluripotent Stem Cell-Derived Basal Forebrain-Like Cholinergic Neurons for Alzheimer’s Disease and Frontotemporal Dementia Disease Modeling“. Cells 9, Nr. 9 (02.09.2020): 2018. http://dx.doi.org/10.3390/cells9092018.

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The study of neurodegenerative diseases using pluripotent stem cells requires new methods to assess neurodevelopment and neurodegeneration of specific neuronal subtypes. The cholinergic system, characterized by its use of the neurotransmitter acetylcholine, is one of the first to degenerate in Alzheimer’s disease and is also affected in frontotemporal dementia. We developed a differentiation protocol to generate basal forebrain-like cholinergic neurons (BFCNs) from induced pluripotent stem cells (iPSCs) aided by the use of small molecule inhibitors and growth factors. Ten iPSC lines were successfully differentiated into BFCNs using this protocol. The neuronal cultures were characterised through RNA and protein expression, and functional analysis of neurons was confirmed by whole-cell patch clamp. We have developed a reliable protocol using only small molecule inhibitors and growth factors, while avoiding transfection or cell sorting methods, to achieve a BFCN culture that expresses the characteristic markers of cholinergic neurons.

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LaBarbera, Kelsie Mozzoni, Colleen Limegrover, Courtney Rehak, Raymond Yurko, Nicholas John Izzo, Nicole Knezovich, Emily Watto, Lora Waybright und Susan M. Catalano. „Modeling the mature CNS: A predictive screening platform for neurodegenerative disease drug discovery“. Journal of Neuroscience Methods 358 (Juli 2021): 109180. http://dx.doi.org/10.1016/j.jneumeth.2021.109180.

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Shahid, Mohammad, Muhammad Shahzad Cheema, Alexander Klenner, Erfan Younesi und Martin Hofmann-Apitius. „SVM Based Descriptor Selection and Classification of Neurodegenerative Disease Drugs for Pharmacological Modeling“. Molecular Informatics 32, Nr. 3 (27.02.2013): 241–49. http://dx.doi.org/10.1002/minf.201200116.

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Yefroyev, David A., und Sha Jin. „Induced Pluripotent Stem Cells for Treatment of Alzheimer’s and Parkinson’s Diseases“. Biomedicines 10, Nr. 2 (19.01.2022): 208. http://dx.doi.org/10.3390/biomedicines10020208.

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Neurodegenerative diseases are a group of debilitating pathologies in which neuronal tissue dies due to the buildup of neurotoxic plaques, resulting in detrimental effects on cognitive ability, motor control, and everyday function. Stem cell technology offers promise in addressing this problem on multiple fronts, but the conventional sourcing of pluripotent stem cells involves harvesting from aborted embryonic tissue, which comes with strong ethical and practical concerns. The keystone discovery of induced pluripotent stem cell (iPSC) technology provides an alternative and endless source, circumventing the unfavorable issues with embryonic stem cells, and yielding fundamental advantages. This review highlights iPSC technology, the pathophysiology of two major neurodegenerative diseases, Alzheimer’s and Parkinson’s, and then illustrates current state-of-the-art approaches towards the treatment of the diseases using iPSCs. The technologies discussed in the review emphasize in vitro therapeutic neural cell and organoid development for disease treatment, pathological modeling of neurodegenerative diseases, and 3D bioprinting as it applies to both.

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Bauer, Susanne, Lars Dittrich, Lech Kaczmarczyk, Melvin Schleif, Rui Benfeitas und Walker S. Jackson. „Translatome profiling in fatal familial insomnia implicates TOR signaling in somatostatin neurons“. Life Science Alliance 5, Nr. 11 (03.10.2022): e202201530. http://dx.doi.org/10.26508/lsa.202201530.

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Selective neuronal vulnerability is common in neurodegenerative diseases but poorly understood. In genetic prion diseases, including fatal familial insomnia (FFI) and Creutzfeldt–Jakob disease (CJD), different mutations in the Prnp gene manifest as clinically and neuropathologically distinct diseases. Here we report with electroencephalography studies that theta waves are mildly increased in 21 mo old knock-in mice modeling FFI and CJD and that sleep is mildy affected in FFI mice. To define affected cell types, we analyzed cell type–specific translatomes from six neuron types of 9 mo old FFI and CJD mice. Somatostatin (SST) neurons responded the strongest in both diseases, with unexpectedly high overlap in genes and pathways. Functional analyses revealed up-regulation of neurodegenerative disease pathways and ribosome and mitochondria biogenesis, and down-regulation of synaptic function and small GTPase-mediated signaling in FFI, implicating down-regulation of mTOR signaling as the root of these changes. In contrast, responses in glutamatergic cerebellar neurons were disease-specific. The high similarity in SST neurons of FFI and CJD mice suggests that a common therapy may be beneficial for multiple genetic prion diseases.

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Zacharias, Helena U., Christoph Kaleta, François Cossais, Eva Schaeffer, Henry Berndt, Lena Best, Thomas Dost et al. „Microbiome and Metabolome Insights into the Role of the Gastrointestinal–Brain Axis in Parkinson’s and Alzheimer’s Disease: Unveiling Potential Therapeutic Targets“. Metabolites 12, Nr. 12 (05.12.2022): 1222. http://dx.doi.org/10.3390/metabo12121222.

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Neurodegenerative diseases such as Parkinson’s (PD) and Alzheimer’s disease (AD), the prevalence of which is rapidly rising due to an aging world population and westernization of lifestyles, are expected to put a strong socioeconomic burden on health systems worldwide. Clinical trials of therapies against PD and AD have only shown limited success so far. Therefore, research has extended its scope to a systems medicine point of view, with a particular focus on the gastrointestinal–brain axis as a potential main actor in disease development and progression. Microbiome and metabolome studies have already revealed important insights into disease mechanisms. Both the microbiome and metabolome can be easily manipulated by dietary and lifestyle interventions, and might thus offer novel, readily available therapeutic options to prevent the onset as well as the progression of PD and AD. This review summarizes our current knowledge on the interplay between microbiota, metabolites, and neurodegeneration along the gastrointestinal–brain axis. We further illustrate state-of-the art methods of microbiome and metabolome research as well as metabolic modeling that facilitate the identification of disease pathomechanisms. We conclude with therapeutic options to modulate microbiome composition to prevent or delay neurodegeneration and illustrate potential future research directions to fight PD and AD.

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Schreiner, Thomas Gabriel, Ioana Creangă-Murariu, Bogdan Ionel Tamba, Nicolae Lucanu und Bogdan Ovidiu Popescu. „In Vitro Modeling of the Blood–Brain Barrier for the Study of Physiological Conditions and Alzheimer’s Disease“. Biomolecules 12, Nr. 8 (18.08.2022): 1136. http://dx.doi.org/10.3390/biom12081136.

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The blood–brain barrier (BBB) is an essential structure for the maintenance of brain homeostasis. Alterations to the BBB are linked with a myriad of pathological conditions and play a significant role in the onset and evolution of neurodegenerative diseases, including Alzheimer’s disease. Thus, a deeper understanding of the BBB’s structure and function is mandatory for a better knowledge of neurodegenerative disorders and the development of effective therapies. Because studying the BBB in vivo imposes overwhelming difficulties, the in vitro approach remains the main possible way of research. With many in vitro BBB models having been developed over the last years, the main aim of this review is to systematically present the most relevant designs used in neurological research. In the first part of the article, the physiological and structural–functional parameters of the human BBB are detailed. Subsequently, available BBB models are presented in a comparative approach, highlighting their advantages and limitations. Finally, the new perspectives related to the study of Alzheimer’s disease with the help of novel devices that mimic the in vivo human BBB milieu gives the paper significant originality.

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Mishima, Takayasu, Shinsuke Fujioka, Jiro Fukae, Junichi Yuasa-Kawada und Yoshio Tsuboi. „Modeling Parkinson’s Disease and Atypical Parkinsonian Syndromes Using Induced Pluripotent Stem Cells“. International Journal of Molecular Sciences 19, Nr. 12 (04.12.2018): 3870. http://dx.doi.org/10.3390/ijms19123870.

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Parkinson’s disease (PD) and atypical parkinsonian syndromes are age-dependent multifactorial neurodegenerative diseases, which are clinically characterized by bradykinesia, tremor, muscle rigidity and postural instability. Although these diseases share several common clinical phenotypes, their pathophysiological aspects vary among the disease categories. Extensive animal-based approaches, as well as postmortem studies, have provided important insights into the disease mechanisms and potential therapeutic targets. However, the exact pathological mechanisms triggering such diseases still remain elusive. Furthermore, the effects of drugs observed in animal models are not always reproduced in human clinical trials. By using induced pluripotent stem cell (iPSC) technology, it has become possible to establish patient-specific iPSCs from their somatic cells and to effectively differentiate these iPSCs into different types of neurons, reproducing some key aspects of the disease phenotypes in vitro. In this review, we summarize recent findings from iPSC-based modeling of PD and several atypical parkinsonian syndromes including multiple system atrophy, frontotemporal dementia and parkinsonism linked to chromosome 17 and Perry syndrome. Furthermore, we discuss future challenges and prospects for modeling and understanding PD and atypical parkinsonian syndromes.

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Pashova-Dimova, Shina, Peter Petrov, Sena Karachanak-Yankova und Anastas Pashov. „Neurodegenerative diseases associated antibody repertoire signatures in mimotope arrays based on cyclic versus linear peptides“. Pharmacia 70, Nr. 4 (30.11.2023): 1439–47. http://dx.doi.org/10.3897/pharmacia.70.e115179.

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The role of peptide probes’ conformational flexibility in extracting immunosignatures has not been sufficiently studied. Immunosignatures profile the antibody diversity and prove promising for early cancer detection and multi-disease diagnostics. A novel tool for modeling antibody repertoires, the concept of antibody reactivity graphs, proved instrumental in this respect. Serum samples from patients with Alzheimer’s disease (AD), frontotemporal dementia (FTD), dementia of unknown etiology (DUE), and healthy controls were probed using a set of 130 7-mer peptides relevant to neurodegenerative diseases. Results show that linear peptides probed with IgM yielded higher graph density compared to IgG, indicating different levels of polyspecificities. Additionally, the impact of peptide topology and antibody isotype on feature selection was studied using recursive feature elimination. Findings reveal that IgM assays on linear peptides offer superior diagnostic differentiation of neurodegenerative diseases and define the degree of agreement between IgG and IgM immunosignatures with linear or cyclic peptides.

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Hegde, Krupa N., und Ajay Srivastava. „Drosophila melanogaster as a Tool for Amyotrophic Lateral Sclerosis Research“. Journal of Developmental Biology 10, Nr. 3 (30.08.2022): 36. http://dx.doi.org/10.3390/jdb10030036.

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Reliable animal model systems are an integral part of biological research. Ever since Thomas Hunt Morgan won a Nobel Prize for genetic work done using the fruit fly (Drosophila melanogaster) as a model organism, it has played a larger and more important role in genetic research. Drosophila models have long been used to study neurodegenerative diseases and have aided in identifying key disease progression biological pathways. Due to the availability of a vast array of genetic manipulation tools, its relatively short lifespan, and its ability to produce many progenies, D. melanogaster has provided the ability to conduct large-scale genetic screens to elucidate possible genetic and molecular interactions in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s Disease, and Amyotrophic Lateral Sclerosis (ALS). With regards to ALS, many of the gene mutations that have been discovered to be linked to the disease have been modeled in Drosophila to provide a look into a detailed model of pathogenesis. The aim of this review is to summarize key and newer developments in ALS research that have utilized Drosophila and to provide insight into the profound use of Drosophila as a tool for modeling this disease.

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Sentyabreva, A. V., E. A. Melnikova, E. A. Miroshnichenko, I. S. Tsvetkov und A. M. Kosyreva. „Morphofunctional changes of microglia in adult and old Wistar rats“. Medical Immunology (Russia) 25, Nr. 3 (01.06.2023): 527–32. http://dx.doi.org/10.15789/1563-0625-mco-2757.

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Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases leading to dementia. There is no effective treatments for this disease so far, as well as a consensus concerning the mechanisms of its pathogenesis initiation. Obtaining data on them in vivo is possible only by modeling neurodegeneration in laboratory animals. Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases leading to dementia. There is no effective treatments for this disease so far, as well as a consensus concerning the mechanisms of its pathogenesis initiation. Obtaining data on them in vivo is possible only by modeling neurodegeneration in laboratory animals. Among the various theories of the initiation of neurodegeneration, the impact of microglia is vigorously studied recently, as well as inflammaging, which is a term for chronic age-related low-grade systemic inflammation. It manifests in the increasing number of senescent cells with senescence-associated secretory phenotype (SASP). Eventually, it leads to manifestation and progression of age-related diseases, such as AD. The aim of the study was to evaluate age-related changes in microglia, pro- and anti-inflammatory cytokines expression levels in the brain, as well as ones of microglial activation, and also subpopulations of lymphocytes in peripheral blood. We used male Wistar rats of two age groups, which were composed of old (age 24 months) and adult (age 3 months) rodents, without any additional exposure. In the hippocampus, morphological changes in microglia were assessed on preparations stained with antibodies to Iba1. In the prefrontal cortex, RT-qPCR was used to study the level of expression of pro-inflammatory IL-6 and TNFa, anti-inflammatory IL-10 and TGF-b cytokines, as well as microglial activation markers iNOS and MMP-9. In the peripheral blood, the relative numbers of the main subpopulations of lymphocytes and monocyte were measured by flow cytometry. It was shown that, compared with adult rats, old animals are characterized by significant changes in the morphology of microglia, an increase in the level of expression of pro-inflammatory and a decrease in anti-inflammatory cytokines, and an increase in microglia activation markers. With aging, a decrease in the percentage of monocytes and B cells in peripheral blood was observed. These data indicate the development of inflammaging, which displays itself in microglia activation, a shift in the balance of cytokine production towards pro-inflammatory ones, and, as a result, activation of the migration of monocytes and B lymphocytes from the blood into tissues. Thus, it is justified to study the role of inflammation in the development of AD in old animals whose physiological state corresponds to that in humans. Further research in this area will expand the understanding of the mechanisms of initiation and progression of neurodegeneration, which is necessary for the development of novel and effective therapeutic approaches to the treatment of AD.

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