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Timofeeva AM, Aulova KS, Nevinsky GA. Modeling Alzheimer's Disease: A Review of Gene-Modified and Induced Animal Models, Complex Cell Culture Models, and Computational Modeling. Brain Sci 2025; 15:486. [PMID: 40426657 PMCID: PMC12109626 DOI: 10.3390/brainsci15050486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2025] [Revised: 04/30/2025] [Accepted: 05/03/2025] [Indexed: 05/29/2025] Open
Abstract
Alzheimer's disease, a complex neurodegenerative disease, is characterized by the pathological aggregation of insoluble amyloid β and hyperphosphorylated tau. Multiple models of this disease have been employed to investigate the etiology, pathogenesis, and multifactorial aspects of Alzheimer's disease and facilitate therapeutic development. Mammals, especially mice, are the most common models for studying the pathogenesis of this disease in vivo. To date, the scientific literature has documented more than 280 mouse models exhibiting diverse aspects of Alzheimer's disease pathogenesis. Other mammalian species, including rats, pigs, and primates, have also been utilized as models. Selected aspects of Alzheimer's disease have also been modeled in simpler model organisms, such as Drosophila melanogaster, Caenorhabditis elegans, and Danio rerio. It is possible to model Alzheimer's disease not only by creating genetically modified animal lines but also by inducing symptoms of this neurodegenerative disease. This review discusses the main methods of creating induced models, with a particular focus on modeling Alzheimer's disease on cell cultures. Induced pluripotent stem cell (iPSC) technology has facilitated novel investigations into the mechanistic underpinnings of diverse diseases, including Alzheimer's. Progress in culturing brain tissue allows for more personalized studies on how drugs affect the brain. Recent years have witnessed substantial advancements in intricate cellular system development, including spheroids, three-dimensional scaffolds, and microfluidic cultures. Microfluidic technologies have emerged as cutting-edge tools for studying intercellular interactions, the tissue microenvironment, and the role of the blood-brain barrier (BBB). Modern biology is experiencing a significant paradigm shift towards utilizing big data and omics technologies. Computational modeling represents a powerful methodology for researching a wide array of human diseases, including Alzheimer's. Bioinformatic methodologies facilitate the analysis of extensive datasets generated via high-throughput experimentation. It is imperative to underscore the significance of integrating diverse modeling techniques in elucidating pathogenic mechanisms in their entirety.
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Affiliation(s)
- Anna M. Timofeeva
- SB RAS Institute of Chemical Biology and Fundamental Medicine, Novosibirsk 630090, Russia
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Rodrigues Salles G, Granato AEC, Viero FT, Pacheco-Soares C, Ferreira ST, Porcionatto M, Ulrich H. Self-assembly and 3D Bioprinting of Neurospheres and Evaluation of Caffeine and Photobiomodulation Effects in an Alzheimer's Disease In Vitro Model. Stem Cell Rev Rep 2025; 21:988-1000. [PMID: 40198478 DOI: 10.1007/s12015-025-10850-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/03/2025] [Indexed: 04/10/2025]
Abstract
Several in vitro models of Alzheimer's disease (AD) rely on 2D cell culture, and, more recently, 3D cultures represented by free-floating neurospheres have been used as models for the disease. The advantage of 3D over 2D cell culture is that cell-extracellular matrix and cell-cell interactions can be assessed, better representing the molecular and cellular hallmarks of the disease. In the current study, we developed two complementary 3D neurosphere models using SH-SY5Y human neuroblastoma cells to investigate AD pathology and evaluate potential therapies. First, self-assembled neurospheres were exposed to hydrogen peroxide (H₂O₂) and amyloid-beta oligomers (AβOs), inducing AD-like features such as increased production of reactive oxygen species (ROS), amyloid aggregation, and apoptosis. Treatment with caffeine or photobiomodulation (PBM) using LED irradiation significantly reduced Aβ1-42 accumulation, ROS generation, and decreased apoptosis markers. Second, 3D bioprinting of SH-SY5Y cells resulted in neurospheres with enhanced cellular organization and differentiation. These findings emphasize the advantages of 3D models for studying neurodegeneration and evaluating therapeutic strategies, bridging the gap between traditional 2D cultures and complex in vitro systems.
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Affiliation(s)
- Geisa Rodrigues Salles
- Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, SP, Brazil
- Institute of Research and Development, University of Vale do Paraíba, São José dos Campos, SP, Brazil
| | - Alessandro E C Granato
- Department of Dental Materials and Prosthodontics, Institute of Science and Technology of São José dos Campos, São Paulo State University (UNESP), São José dos Campos, SP, Brazil
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, Av. Prof. Lineu Prestes 748, São Paulo, 05508-900, SP, Brazil
| | - Fernanda Tibolla Viero
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, Av. Prof. Lineu Prestes 748, São Paulo, 05508-900, SP, Brazil
| | - Cristina Pacheco-Soares
- Institute of Research and Development, University of Vale do Paraíba, São José dos Campos, SP, Brazil
| | - Sérgio T Ferreira
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- D'Or Institute for Research and Education, Rio de Janeiro, RJ, Brazil
| | - Marimelia Porcionatto
- Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, SP, Brazil
- National Institute of Science and Technology in Modeling Human Complex Diseases with 3D Platforms (INCT Model3D), São Paulo, SP, Brazil
| | - Henning Ulrich
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, Av. Prof. Lineu Prestes 748, São Paulo, 05508-900, SP, Brazil.
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Shamul JG, Wang Z, Gong H, Ou W, White AM, Moniz-Garcia DP, Gu S, Clyne AM, Quiñones-Hinojosa A, He X. Meta-analysis of the make-up and properties of in vitro models of the healthy and diseased blood-brain barrier. Nat Biomed Eng 2025; 9:566-598. [PMID: 39304761 PMCID: PMC11922799 DOI: 10.1038/s41551-024-01250-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 08/08/2024] [Indexed: 09/22/2024]
Abstract
In vitro models of the human blood-brain barrier (BBB) are increasingly used to develop therapeutics that can cross the BBB for treating diseases of the central nervous system. Here we report a meta-analysis of the make-up and properties of transwell and microfluidic models of the healthy BBB and of BBBs in glioblastoma, Alzheimer's disease, Parkinson's disease and inflammatory diseases. We found that the type of model, the culture method (static or dynamic), the cell types and cell ratios, and the biomaterials employed as extracellular matrix are all crucial to recapitulate the low permeability and high expression of tight-junction proteins of the BBB, and to obtain high trans-endothelial electrical resistance. Specifically, for models of the healthy BBB, the inclusion of endothelial cells and pericytes as well as physiological shear stresses (~10-20 dyne cm-2) are necessary, and when astrocytes are added, astrocytes or pericytes should outnumber endothelial cells. We expect this meta-analysis to facilitate the design of increasingly physiological models of the BBB.
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Affiliation(s)
- James G Shamul
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA
- RNA Mediated Gene Regulation Section, RNA Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA
| | - Zhiyuan Wang
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA
| | - Hyeyeon Gong
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA
| | - Wenquan Ou
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA
| | - Alisa M White
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA
| | | | - Shuo Gu
- RNA Mediated Gene Regulation Section, RNA Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA
| | - Alisa Morss Clyne
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA
- Robert E. Fischell Institute for Biomedical Devices, University of Maryland, College Park, MD, USA
- Brain and Behavior Institute, University of Maryland, College Park, MD, USA
| | | | - Xiaoming He
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA.
- Robert E. Fischell Institute for Biomedical Devices, University of Maryland, College Park, MD, USA.
- Brain and Behavior Institute, University of Maryland, College Park, MD, USA.
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, USA.
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Qi X, Nizamutdinov D, Yi SS, Wu E, Huang JH. Disease Modifying Monoclonal Antibodies and Symptomatic Pharmacological Treatment for Alzheimer's Disease. Biomedicines 2024; 12:2636. [PMID: 39595200 PMCID: PMC11592475 DOI: 10.3390/biomedicines12112636] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 11/08/2024] [Accepted: 11/14/2024] [Indexed: 11/28/2024] Open
Abstract
Alzheimer's Disease (AD) is an irreversible, progressive syndrome characterized by neurocognitive impairment. Two neuropathological features seen in AD are extracellular amyloid plaques consisting of amyloid beta1-40 and 1-42, and intracellular neurofibrillary tangles (NFTs). For decades, neuroscience research has heavily focused on seeking to understand the primary mechanism of AD and searching for pharmacological approaches for the treatment of dementia. Three monoclonal antibodies that act against amyloid beta-aducanumab, lecanemab, and donanemab-have been approved by the Food and Drug Administration (FDA) for the treatment of mild cognitive impairment and mild AD, in addition to medications for cognitive symptom management such as acetylcholinesterase inhibitors and the N-methyl-D-aspartate (NMDA) antagonist. Further trials should focus on the combination of therapies targeting amyloid plaques and tau pathology.
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Affiliation(s)
- Xiaoming Qi
- Department of Neurology, Baylor Scott & White Health, Temple, TX 78508, USA;
| | - Damir Nizamutdinov
- Department of Neurosurgery, Neuroscience Institute, Baylor Scott & White Health, Temple, TX 78508, USA; (D.N.); (S.S.Y.); (E.W.)
| | - Song Stephen Yi
- Department of Neurosurgery, Neuroscience Institute, Baylor Scott & White Health, Temple, TX 78508, USA; (D.N.); (S.S.Y.); (E.W.)
| | - Erxi Wu
- Department of Neurosurgery, Neuroscience Institute, Baylor Scott & White Health, Temple, TX 78508, USA; (D.N.); (S.S.Y.); (E.W.)
- Department of Neurosurgery, Baylor College of Medicine, Temple, TX 76508, USA
- College of Medicine, Texas A&M University, College Station, TX 77843, USA
- College of Irma Lerma Rangel College of Pharmacy, Texas A&M University, College Station, TX 77843, USA
- LIVESTRONG Cancer Institutes, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA
| | - Jason H. Huang
- Department of Neurosurgery, Neuroscience Institute, Baylor Scott & White Health, Temple, TX 78508, USA; (D.N.); (S.S.Y.); (E.W.)
- Department of Neurosurgery, Baylor College of Medicine, Temple, TX 76508, USA
- College of Medicine, Texas A&M University, College Station, TX 77843, USA
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Cui X, Li X, Zheng H, Su Y, Zhang S, Li M, Hao X, Zhang S, Hu Z, Xia Z, Shi C, Xu Y, Mao C. Human midbrain organoids: a powerful tool for advanced Parkinson's disease modeling and therapy exploration. NPJ Parkinsons Dis 2024; 10:189. [PMID: 39428415 PMCID: PMC11491477 DOI: 10.1038/s41531-024-00799-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 10/02/2024] [Indexed: 10/22/2024] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder marked by the loss of dopaminergic neurons in the substantia nigra. Despite progress, the pathogenesis remains unclear. Human midbrain organoids (hMLOs) have emerged as a promising model for studying PD, drug screening, and potential treatments. This review discusses the development of hMLOs, their application in PD research, and current challenges in organoid construction, highlighting possible optimization strategies.
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Affiliation(s)
- Xin Cui
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Academy of Medical Sciences of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Xinwei Li
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Academy of Medical Sciences of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Huimin Zheng
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Yun Su
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Shuyu Zhang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Neuro-Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Mengjie Li
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Xiaoyan Hao
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Shuo Zhang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Academy of Medical Sciences of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Zhengwei Hu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Academy of Medical Sciences of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Zongping Xia
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Clinical Systems Biology Laboratories, Zhengzhou University, Zhengzhou, China
| | - Changhe Shi
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Institute of Neuroscience, Zhengzhou University, Zhengzhou, China
| | - Yuming Xu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
- Institute of Neuroscience, Zhengzhou University, Zhengzhou, China.
| | - Chengyuan Mao
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
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Briglia M, Allia F, Avola R, Signorini C, Cardile V, Romano GL, Giurdanella G, Malaguarnera R, Bellomo M, Graziano ACE. Diet and Nutrients in Rare Neurological Disorders: Biological, Biochemical, and Pathophysiological Evidence. Nutrients 2024; 16:3114. [PMID: 39339713 PMCID: PMC11435074 DOI: 10.3390/nu16183114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2024] [Revised: 09/12/2024] [Accepted: 09/12/2024] [Indexed: 09/30/2024] Open
Abstract
Background/Objectives: Rare diseases are a wide and heterogeneous group of multisystem life-threatening or chronically debilitating clinical conditions with reduced life expectancy and a relevant mortality rate in childhood. Some of these disorders have typical neurological symptoms, presenting from birth to adulthood. Dietary patterns and nutritional compounds play key roles in the onset and progression of neurological disorders, and the impact of alimentary needs must be enlightened especially in rare neurological diseases. This work aims to collect the in vitro, in vivo, and clinical evidence on the effects of diet and of nutrient intake on some rare neurological disorders, including some genetic diseases, and rare brain tumors. Herein, those aspects are critically linked to the genetic, biological, biochemical, and pathophysiological hallmarks typical of each disorder. Methods: By searching the major web-based databases (PubMed, Web of Science Core Collection, DynaMed, and Clinicaltrials.gov), we try to sum up and improve our understanding of the emerging role of nutrition as both first-line therapy and risk factors in rare neurological diseases. Results: In line with the increasing number of consensus opinions suggesting that nutrients should receive the same attention as pharmacological treatments, the results of this work pointed out that a standard dietary recommendation in a specific rare disease is often limited by the heterogeneity of occurrent genetic mutations and by the variability of pathophysiological manifestation. Conclusions: In conclusion, we hope that the knowledge gaps identified here may inspire further research for a better evaluation of molecular mechanisms and long-term effects.
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Affiliation(s)
- Marilena Briglia
- Department of Medicine and Surgery, “Kore” University of Enna, 94100 Enna, Italy; (M.B.); (F.A.); (R.A.); (G.L.R.); (R.M.); (M.B.)
| | - Fabio Allia
- Department of Medicine and Surgery, “Kore” University of Enna, 94100 Enna, Italy; (M.B.); (F.A.); (R.A.); (G.L.R.); (R.M.); (M.B.)
| | - Rosanna Avola
- Department of Medicine and Surgery, “Kore” University of Enna, 94100 Enna, Italy; (M.B.); (F.A.); (R.A.); (G.L.R.); (R.M.); (M.B.)
| | - Cinzia Signorini
- Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy;
| | - Venera Cardile
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy;
| | - Giovanni Luca Romano
- Department of Medicine and Surgery, “Kore” University of Enna, 94100 Enna, Italy; (M.B.); (F.A.); (R.A.); (G.L.R.); (R.M.); (M.B.)
| | - Giovanni Giurdanella
- Department of Medicine and Surgery, “Kore” University of Enna, 94100 Enna, Italy; (M.B.); (F.A.); (R.A.); (G.L.R.); (R.M.); (M.B.)
| | - Roberta Malaguarnera
- Department of Medicine and Surgery, “Kore” University of Enna, 94100 Enna, Italy; (M.B.); (F.A.); (R.A.); (G.L.R.); (R.M.); (M.B.)
| | - Maria Bellomo
- Department of Medicine and Surgery, “Kore” University of Enna, 94100 Enna, Italy; (M.B.); (F.A.); (R.A.); (G.L.R.); (R.M.); (M.B.)
| | - Adriana Carol Eleonora Graziano
- Department of Medicine and Surgery, “Kore” University of Enna, 94100 Enna, Italy; (M.B.); (F.A.); (R.A.); (G.L.R.); (R.M.); (M.B.)
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Kuhn MK, Proctor EA. Microglial Drivers of Alzheimer's Disease Pathology: An Evolution of Diverse Participating States. Proteins 2024:10.1002/prot.26723. [PMID: 39219300 PMCID: PMC11871049 DOI: 10.1002/prot.26723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 06/05/2024] [Accepted: 06/12/2024] [Indexed: 09/04/2024]
Abstract
Microglia, the resident immune-competent cells of the brain, become dysfunctional in Alzheimer's disease (AD), and their aberrant immune responses contribute to the accumulation of pathological proteins and neuronal injury. Genetic studies implicate microglia in the development of AD, prompting interest in developing immunomodulatory therapies to prevent or ameliorate disease. However, microglia take on diverse functional states in disease, playing both protective and detrimental roles in AD, which largely overlap and may shift over the disease course, complicating the identification of effective therapeutic targets. Extensive evidence gathered using transgenic mouse models supports an active role of microglia in pathology progression, though results vary and can be contradictory between different types of models and the degree of pathology at the time of study. Here, we review microglial immune signaling and responses that contribute to the accumulation and spread of pathological proteins or directly affect neuronal health. We additionally explore the use of induced pluripotent stem cell (iPSC)-derived models to study living human microglia and how they have contributed to our knowledge of AD and may begin to fill in the gaps left by mouse models. Ultimately, mouse and iPSC-derived models have their own limitations, and a comprehensive understanding of microglial dysfunction in AD will only be established by an integrated view across models and an appreciation for their complementary viewpoints and limitations.
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Affiliation(s)
- Madison K. Kuhn
- Department of Biomedical Engineering, Penn State University
- Department of Neurosurgery, Penn State College of Medicine
- Department of Pharmacology, Penn State College of Medicine
- Center for Neural Engineering, Penn State University
| | - Elizabeth A. Proctor
- Department of Biomedical Engineering, Penn State University
- Department of Neurosurgery, Penn State College of Medicine
- Department of Pharmacology, Penn State College of Medicine
- Center for Neural Engineering, Penn State University
- Department of Engineering Science & Mechanics, Penn State University
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Fernandes S, Revanna J, Pratt J, Hayes N, Marchetto MC, Gage FH. Modeling Alzheimer's disease using human cell derived brain organoids and 3D models. Front Neurosci 2024; 18:1434945. [PMID: 39156632 PMCID: PMC11328153 DOI: 10.3389/fnins.2024.1434945] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Accepted: 07/10/2024] [Indexed: 08/20/2024] Open
Abstract
Age-related neurodegenerative diseases, like Alzheimer's disease (AD), are challenging diseases for those affected with no cure and limited treatment options. Functional, human derived brain tissues that represent the diverse genetic background and cellular subtypes contributing to sporadic AD (sAD) are limited. Human stem cell derived brain organoids recapitulate some features of human brain cytoarchitecture and AD-like pathology, providing a tool for illuminating the relationship between AD pathology and neural cell dysregulation leading to cognitive decline. In this review, we explore current strategies for implementing brain organoids in the study of AD as well as the challenges associated with investigating age-related brain diseases using organoid models.
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Affiliation(s)
- Sarah Fernandes
- Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, United States
- Department of Biological Sciences, University of California, San Diego, La Jolla, CA, United States
| | - Jasmin Revanna
- Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, United States
- Department of Biological Sciences, University of California, San Diego, La Jolla, CA, United States
| | - Joshua Pratt
- Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, United States
- Department of Biology, San Diego State University, San Diego, CA, United States
| | - Nicholas Hayes
- Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, United States
- Department of Biological Sciences, California State University, San Marcos, CA, United States
| | - Maria C. Marchetto
- Department of Anthropology, Center for Academic Research and Training in Anthropogeny (CARTA), University of California, San Diego, La Jolla, CA, United States
| | - Fred H. Gage
- Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, United States
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Choe MS, Yeo HC, Kim JS, Lee J, Lee HJ, Kim HR, Baek KM, Jung NY, Choi M, Lee MY. Simple modeling of familial Alzheimer's disease using human pluripotent stem cell-derived cerebral organoid technology. Stem Cell Res Ther 2024; 15:118. [PMID: 38659053 PMCID: PMC11040922 DOI: 10.1186/s13287-024-03732-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 04/12/2024] [Indexed: 04/26/2024] Open
Abstract
BACKGROUND Cerebral organoids (COs) are the most advanced in vitro models that resemble the human brain. The use of COs as a model for Alzheimer's disease (AD), as well as other brain diseases, has recently gained attention. This study aimed to develop a human AD CO model using normal human pluripotent stem cells (hPSCs) that recapitulates the pathological phenotypes of AD and to determine the usefulness of this model for drug screening. METHODS We established AD hPSC lines from normal hPSCs by introducing genes that harbor familial AD mutations, and the COs were generated using these hPSC lines. The pathological features of AD, including extensive amyloid-β (Aβ) accumulation, tauopathy, and neurodegeneration, were analyzed using enzyme-linked immunosorbent assay, Amylo-Glo staining, thioflavin-S staining, immunohistochemistry, Bielschowsky's staining, and western blot analysis. RESULTS The AD COs exhibited extensive Aβ accumulation. The levels of paired helical filament tau and neurofibrillary tangle-like silver deposits were highly increased in the AD COs. The number of cells immunoreactive for cleaved caspase-3 was significantly increased in the AD COs. In addition, treatment of AD COs with BACE1 inhibitor IV, a β-secretase inhibitor, and compound E, a γ-secretase inhibitor, significantly attenuated the AD pathological features. CONCLUSION Our model effectively recapitulates AD pathology. Hence, it is a valuable platform for understanding the mechanisms underlying AD pathogenesis and can be used to test the efficacy of anti-AD drugs.
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Affiliation(s)
- Mu Seog Choe
- Department of Molecular Physiology, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Vessel-Organ Interaction Research Center (VOICE, MRC), Kyungpook National University, 41566, Daegu, Republic of Korea
| | - Han Cheol Yeo
- Department of Molecular Physiology, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Vessel-Organ Interaction Research Center (VOICE, MRC), Kyungpook National University, 41566, Daegu, Republic of Korea
| | - Joong Sun Kim
- Department of Veterinary Anatomy, College of Veterinary Medicine, Chonnam National University, 61186, Gwangju, Republic of Korea
| | - Jean Lee
- Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, 03080, Seoul, Republic of Korea
| | - Hae Jun Lee
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences (KIRAMS), 01812, Seoul, Republic of Korea
| | - Hyung-Ryong Kim
- Department of Pharmacology, College of Dentistry, Jeonbuk National University, 54896, Jeonju, Republic of Korea
| | - Kyung Min Baek
- Department of Cardiovascular and Neurologic Disease, College of Oriental Medicine, Daegu Haany University, 42158, Daegu, Republic of Korea
| | - Na-Yeon Jung
- Department of Neurology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, 50612, Yangsan, Republic of Korea
| | - Murim Choi
- Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, 03080, Seoul, Republic of Korea.
| | - Min Young Lee
- Department of Molecular Physiology, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Vessel-Organ Interaction Research Center (VOICE, MRC), Kyungpook National University, 41566, Daegu, Republic of Korea.
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10
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Birkle TJ, Willems HM, Skidmore J, Brown GC. Disease phenotypic screening in neuron-glia cocultures identifies blockers of inflammatory neurodegeneration. iScience 2024; 27:109454. [PMID: 38550989 PMCID: PMC10973195 DOI: 10.1016/j.isci.2024.109454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 10/09/2023] [Accepted: 03/06/2024] [Indexed: 01/30/2025] Open
Abstract
Neuropathology is often mediated by interactions between neurons and glia that cannot be modeled by monocultures. However, cocultures are difficult to use and analyze for high-content screening. Here, we perform compound screening using primary neuron-glia cultures to model inflammatory neurodegeneration, live-cell stains, and automated classification of neurons, astrocytes or microglia using open-source software. Out of 227 compounds with known bioactivities, 29 protected against lipopolysaccharide-induced neuronal loss, including drugs affecting adrenergic, steroid, inflammatory and MAP kinase signaling. The screen also identified physiological compounds, such as noradrenaline and progesterone, that protected and identified neurotoxic compounds, such as a TLR7 agonist, that induced microglial proliferation. Most compounds used here have not been tested in a neuron-glia coculture neurodegeneration assay previously. Thus, combining a complex cellular disease model with high-content screening of known compounds and automated image analysis allows identification of important biology, as well as potential targets and drugs for treatment.
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Affiliation(s)
| | | | - John Skidmore
- ALBORADA Drug Discovery Institute, Cambridge CB2 0AH, UK
| | - Guy C. Brown
- Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK
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11
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Balestri W, Sharma R, da Silva VA, Bobotis BC, Curle AJ, Kothakota V, Kalantarnia F, Hangad MV, Hoorfar M, Jones JL, Tremblay MÈ, El-Jawhari JJ, Willerth SM, Reinwald Y. Modeling the neuroimmune system in Alzheimer's and Parkinson's diseases. J Neuroinflammation 2024; 21:32. [PMID: 38263227 PMCID: PMC10807115 DOI: 10.1186/s12974-024-03024-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 01/16/2024] [Indexed: 01/25/2024] Open
Abstract
Parkinson's disease (PD) and Alzheimer's disease (AD) are neurodegenerative disorders caused by the interaction of genetic, environmental, and familial factors. These diseases have distinct pathologies and symptoms that are linked to specific cell populations in the brain. Notably, the immune system has been implicated in both diseases, with a particular focus on the dysfunction of microglia, the brain's resident immune cells, contributing to neuronal loss and exacerbating symptoms. Researchers use models of the neuroimmune system to gain a deeper understanding of the physiological and biological aspects of these neurodegenerative diseases and how they progress. Several in vitro and in vivo models, including 2D cultures and animal models, have been utilized. Recently, advancements have been made in optimizing these existing models and developing 3D models and organ-on-a-chip systems, holding tremendous promise in accurately mimicking the intricate intracellular environment. As a result, these models represent a crucial breakthrough in the transformation of current treatments for PD and AD by offering potential for conducting long-term disease-based modeling for therapeutic testing, reducing reliance on animal models, and significantly improving cell viability compared to conventional 2D models. The application of 3D and organ-on-a-chip models in neurodegenerative disease research marks a prosperous step forward, providing a more realistic representation of the complex interactions within the neuroimmune system. Ultimately, these refined models of the neuroimmune system aim to aid in the quest to combat and mitigate the impact of debilitating neuroimmune diseases on patients and their families.
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Affiliation(s)
- Wendy Balestri
- Department of Engineering, School of Science and Technology, Nottingham Trent University, Nottingham, UK
- Medical Technologies Innovation Facility, Nottingham Trent University, Nottingham, UK
| | - Ruchi Sharma
- Department of Mechanical Engineering, University of Victoria, Victoria, Canada
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Centre for Advanced Materials and Related Technology (CAMTEC), University of Victoria, Victoria, BC, Canada
| | - Victor A da Silva
- Department of Mechanical Engineering, University of Victoria, Victoria, Canada
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Centre for Advanced Materials and Related Technology (CAMTEC), University of Victoria, Victoria, BC, Canada
| | - Bianca C Bobotis
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Centre for Advanced Materials and Related Technology (CAMTEC), University of Victoria, Victoria, BC, Canada
| | - Annabel J Curle
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Vandana Kothakota
- Department of Biosciences, School of Science and Technology, Nottingham Trent University, Nottingham, UK
| | | | - Maria V Hangad
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Centre for Advanced Materials and Related Technology (CAMTEC), University of Victoria, Victoria, BC, Canada
- Department of Chemistry, University of Victoria, Victoria, BC, Canada
| | - Mina Hoorfar
- Department of Mechanical Engineering, University of Victoria, Victoria, Canada
| | - Joanne L Jones
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Marie-Ève Tremblay
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Centre for Advanced Materials and Related Technology (CAMTEC), University of Victoria, Victoria, BC, Canada
- Neurosciences Axis, Centre de Recherche du CHU de Québec, Université Laval, Québec City, QC, Canada
- Department of Molecular Medicine, Université Laval, Québec City, QC, Canada
- Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, BC, Canada
- Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada
- Institute On Aging and Lifelong Health, University of Victoria, Victoria, BC, Canada
| | - Jehan J El-Jawhari
- Department of Biosciences, School of Science and Technology, Nottingham Trent University, Nottingham, UK
- Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Stephanie M Willerth
- Department of Mechanical Engineering, University of Victoria, Victoria, Canada.
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada.
- Centre for Advanced Materials and Related Technology (CAMTEC), University of Victoria, Victoria, BC, Canada.
- School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada.
| | - Yvonne Reinwald
- Department of Engineering, School of Science and Technology, Nottingham Trent University, Nottingham, UK.
- Medical Technologies Innovation Facility, Nottingham Trent University, Nottingham, UK.
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12
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Pereira I, Lopez-Martinez MJ, Samitier J. Advances in current in vitro models on neurodegenerative diseases. Front Bioeng Biotechnol 2023; 11:1260397. [PMID: 38026882 PMCID: PMC10658011 DOI: 10.3389/fbioe.2023.1260397] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 10/23/2023] [Indexed: 12/01/2023] Open
Abstract
Many neurodegenerative diseases are identified but their causes and cure are far from being well-known. The problem resides in the complexity of the neural tissue and its location which hinders its easy evaluation. Although necessary in the drug discovery process, in vivo animal models need to be reduced and show relevant differences with the human tissues that guide scientists to inquire about other possible options which lead to in vitro models being explored. From organoids to organ-on-a-chips, 3D models are considered the cutting-edge technology in cell culture. Cell choice is a big parameter to take into consideration when planning an in vitro model and cells capable of mimicking both healthy and diseased tissue, such as induced pluripotent stem cells (iPSC), are recognized as good candidates. Hence, we present a critical review of the latest models used to study neurodegenerative disease, how these models have evolved introducing microfluidics platforms, 3D cell cultures, and the use of induced pluripotent cells to better mimic the neural tissue environment in pathological conditions.
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Affiliation(s)
- Inês Pereira
- Nanobioengineering Group, Institute for Bioengineering of Catalonia, Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Maria J. Lopez-Martinez
- Nanobioengineering Group, Institute for Bioengineering of Catalonia, Barcelona Institute of Science and Technology, Barcelona, Spain
- Centro Investigación Biomédica en Red: Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Department of Electronics and Biomedical Engineering, University of Barcelona, Barcelona, Spain
| | - Josep Samitier
- Nanobioengineering Group, Institute for Bioengineering of Catalonia, Barcelona Institute of Science and Technology, Barcelona, Spain
- Centro Investigación Biomédica en Red: Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Department of Electronics and Biomedical Engineering, University of Barcelona, Barcelona, Spain
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13
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Delage E, Guilbert T, Yates F. Successful 3D imaging of cleared biological samples with light sheet fluorescence microscopy. J Cell Biol 2023; 222:e202307143. [PMID: 37847528 PMCID: PMC10583220 DOI: 10.1083/jcb.202307143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 09/22/2023] [Accepted: 09/22/2023] [Indexed: 10/18/2023] Open
Abstract
In parallel with the development of tissue-clearing methods, over the last decade, light sheet fluorescence microscopy has contributed to major advances in various fields, such as cell and developmental biology and neuroscience. While biologists are increasingly integrating three-dimensional imaging into their research projects, their experience with the technique is not always up to their expectations. In response to a survey of specific challenges associated with sample clearing and labeling, image acquisition, and data analysis, we have critically assessed the recent literature to characterize the difficulties inherent to light sheet fluorescence microscopy applied to cleared biological samples and to propose solutions to overcome them. This review aims to provide biologists interested in light sheet fluorescence microscopy with a primer for the development of their imaging pipeline, from sample preparation to image analysis. Importantly, we believe that issues could be avoided with better anticipation of image analysis requirements, which should be kept in mind while optimizing sample preparation and acquisition parameters.
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Affiliation(s)
- Elise Delage
- CellTechs Laboratory, SupBiotech, Villejuif, France
- Service d’Etude des Prions et des Infections Atypiques, Institut François Jacob, Commissariat à l’Energie Atomique et aux Energies Alternatives, Université Paris Saclay, Fontenay-aux-Roses, France
| | - Thomas Guilbert
- Institut Cochin, Institut national de la santé et de la recherche médicale (U1016), Centre National de la Recherche Scientifique (UMR 8104), Université de Paris (UMR-S1016), Paris, France
| | - Frank Yates
- CellTechs Laboratory, SupBiotech, Villejuif, France
- Service d’Etude des Prions et des Infections Atypiques, Institut François Jacob, Commissariat à l’Energie Atomique et aux Energies Alternatives, Université Paris Saclay, Fontenay-aux-Roses, France
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14
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Alawad AO, Alagrafi FS, Alfahad AJ, Alamari HA, Alghamdi FO, Fallatah HM, Aodah AH, Alyousef SS, Bakhrebah MA, Alanazi IO, Fallatah MM. Effects of Rhazya Stricta plant organic extracts on human induced pluripotent stem cells derived neural stem cells. PLoS One 2023; 18:e0288032. [PMID: 37478090 PMCID: PMC10361509 DOI: 10.1371/journal.pone.0288032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Accepted: 06/18/2023] [Indexed: 07/23/2023] Open
Abstract
Rhazya Stricta (R. stricta) has been employed as a natural remedy for several diseases for centuries. Numerous studies revealed that R. stricta extracts contain alkaloids, tannins, and flavonoids that possess antimicrobial, anticancer, antihypertensive, and antioxidant activities. In this study, we examined the effects of organic extracts from different parts of R. stricta plant on human pluripotent stem cells (hiPSCs)-derived neural stem cells (NSCs) for medical purposes. NSCs were incubated with different concentrations of organic extracts from the leaves, stem, and fruits, and we assessed the growth and viability of the cells by using MTS assay and the chemical composition of the potential plant extract by using gas chromatography-mass spectrometry (GC/MS). Our results revealed that the methanolic extract from the stem increased NSCs growth significantly, particularly at a concentration of 25 μg/ml. GC/MS analysis was utilized to identify the potential compounds of the methanolic extract. In conclusion, our results demonstrated for the first time that methanolic stem extract of R. stricta contains compounds that can positively impact NSCs growth. These compounds can be further investigated to determine the potential bioactive compounds that can be used for research and medical purposes.
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Affiliation(s)
- Abdullah Othman Alawad
- Aging Institute, Health Sector, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
| | - Faisal Sultan Alagrafi
- Aging Institute, Health Sector, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
| | - Ahmed Jaman Alfahad
- Bioengineering Institute, Health Sector, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
| | - Hala Abdulrahman Alamari
- Bioengineering Institute, Health Sector, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
| | - Fatimah Othman Alghamdi
- Bioengineering Institute, Health Sector, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
| | - Hussam Mokhtar Fallatah
- Waste Management and Recycling Institute, Sustainability and Environment Sector, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
| | - Alhassan Hamood Aodah
- Advanced Diagnostics and Therapeutics Technologies Institute, Health Sector, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
| | - Sultan Suleiman Alyousef
- Advanced Diagnostics and Therapeutics Technologies Institute, Health Sector, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
| | - Muhammed Adnan Bakhrebah
- Advanced Diagnostics and Therapeutics Technologies Institute, Health Sector, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
| | - Ibrahim Oqla Alanazi
- Aging Institute, Health Sector, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
| | - Mohannad Mokhtar Fallatah
- Advanced Diagnostics and Therapeutics Technologies Institute, Health Sector, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
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15
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Jeyaraman M, Rajendran RL, Muthu S, Jeyaraman N, Sharma S, Jha SK, Muthukanagaraj P, Hong CM, Furtado da Fonseca L, Santos Duarte Lana JF, Ahn BC, Gangadaran P. An update on stem cell and stem cell-derived extracellular vesicle-based therapy in the management of Alzheimer's disease. Heliyon 2023; 9:e17808. [PMID: 37449130 PMCID: PMC10336689 DOI: 10.1016/j.heliyon.2023.e17808] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 05/10/2023] [Accepted: 06/28/2023] [Indexed: 07/18/2023] Open
Abstract
Globally, neurological diseases pose a major burden to healthcare professionals in terms of the management and prevention of the disorder. Among neurological diseases, Alzheimer's disease (AD) accounts for 50%-70% of dementia and is the fifth leading cause of mortality worldwide. AD is a progressive, degenerative neurological disease, with the loss of neurons and synapses in the cerebral cortex and subcortical regions. The management of AD remains a debate among physicians as no standard and specific "disease-modifying" modality is available. The concept of 'Regenerative Medicine' is aimed at regenerating the degenerated neural tissues to reverse the pathology in AD. Genetically modified engineered stem cells modify the course of AD after transplantation into the brain. Extracellular vesicles (EVs) are an emerging new approach in cell communication that involves the transfer of cellular materials from parental cells to recipient cells, resulting in changes at the molecular and signaling levels in the recipient cells. EVs are a type of vesicle that can be transported between cells. Many have proposed that EVs produced from mesenchymal stem cells (MSCs) may have therapeutic promise in the treatment of AD. The biology of AD, as well as the potential applications of stem cells and their derived EVs-based therapy, were explored in this paper.
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Affiliation(s)
- Madhan Jeyaraman
- Department of Orthopaedics, ACS Medical College and Hospital, Dr MGR Educational and Research Institute, Chennai, Tamil Nadu, 600056, India
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh, 201310, India
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow, Uttar Pradesh, 226010, India
| | - Ramya Lakshmi Rajendran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, 41944, Republic of Korea
| | - Sathish Muthu
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh, 201310, India
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow, Uttar Pradesh, 226010, India
- Department of Orthopedics, Government Dindigul Medical College and Hospital, Dindigul, Tamil Nadu, 624001, India
| | - Naveen Jeyaraman
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow, Uttar Pradesh, 226010, India
- Department of Orthopedics, Shri Sathya Sai Medical College and Research Institute, Sri Balaji Vidyapeeth, Chengalpet, Tamil Nadu, 603108, India
| | - Shilpa Sharma
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow, Uttar Pradesh, 226010, India
- Department of Paediatric Surgery, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Saurabh Kumar Jha
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh, 201310, India
| | - Purushothaman Muthukanagaraj
- Department of Internal Medicine & Psychiatry, SUNY-Upstate Binghamton Clinical Campus, Binghamton, NY, 13904, USA
| | - Chae Moon Hong
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, 41944, Republic of Korea
| | - Lucas Furtado da Fonseca
- Department of Orthopedics, The Federal University of São Paulo, São Paulo, 04023-062, SP, Brazil
| | | | - Byeong-Cheol Ahn
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, 41944, Republic of Korea
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Sciences, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea
| | - Prakash Gangadaran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, 41944, Republic of Korea
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Sciences, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea
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16
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Benwood C, Walters-Shumka J, Scheck K, Willerth SM. 3D bioprinting patient-derived induced pluripotent stem cell models of Alzheimer's disease using a smart bioink. Bioelectron Med 2023; 9:10. [PMID: 37221543 DOI: 10.1186/s42234-023-00112-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 05/09/2023] [Indexed: 05/25/2023] Open
Abstract
BACKGROUND Alzheimer's disease (AD), a progressive neurodegenerative disorder, is becoming increasingly prevalent as our population ages. It is characterized by the buildup of amyloid beta plaques and neurofibrillary tangles containing hyperphosphorylated-tau. The current treatments for AD do not prevent the long-term progression of the disease and pre-clinical models often do not accurately represent its complexity. Bioprinting combines cells and biomaterials to create 3D structures that replicate the native tissue environment and can be used as a tool in disease modeling or drug screening. METHODS This work differentiated both healthy and diseased patient-derived human induced pluripotent stems cells (hiPSCs) into neural progenitor cells (NPCs) that were bioprinted using the Aspect RX1 microfluidic printer into dome-shaped constructs. The combination of cells, bioink, and puromorphamine (puro)-releasing microspheres were used to mimic the in vivo environment and direct the differentiation of the NPCs into basal forebrain-resembling cholinergic neurons (BFCN). These tissue models were then characterized for cell viability, immunocytochemistry, and electrophysiology to evaluate their functionality and physiology for use as disease-specific neural models. RESULTS Tissue models were successfully bioprinted and the cells were viable for analysis after 30- and 45-day cultures. The neuronal and cholinergic markers β-tubulin III (Tuj1), forkhead box G1 (FOXG1), and choline acetyltransferase (ChAT) were identified as well as the AD markers amyloid beta and tau. Further, immature electrical activity was observed when the cells were excited with potassium chloride and acetylcholine. CONCLUSIONS This work shows the successful development of bioprinted tissue models incorporating patient derived hiPSCs. Such models can potentially be used as a tool to screen promising drug candidates for treating AD. Further, this model could be used to increase the understanding of AD progression. The use of patient derived cells also shows the potential of this model for use in personalized medicine applications.
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Affiliation(s)
- Claire Benwood
- Department of Mechanical Engineering, University of Victoria, Victoria, BC, V8P 5C2, Canada
| | | | - Kali Scheck
- Division of Medical Sciences, University of Victoria, Victoria, BC, V8P 5C2, Canada
| | - Stephanie M Willerth
- Department of Mechanical Engineering, University of Victoria, Victoria, BC, V8P 5C2, Canada.
- Division of Medical Sciences, University of Victoria, Victoria, BC, V8P 5C2, Canada.
- School of Biomedical Engineering, The University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
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17
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Kostes WW, Brafman DA. The Multifaceted Role of WNT Signaling in Alzheimer's Disease Onset and Age-Related Progression. Cells 2023; 12:1204. [PMID: 37190113 PMCID: PMC10136584 DOI: 10.3390/cells12081204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 04/12/2023] [Accepted: 04/17/2023] [Indexed: 05/17/2023] Open
Abstract
The evolutionary conserved WNT signaling pathway orchestrates numerous complex biological processes during development and is critical to the maintenance of tissue integrity and homeostasis in the adult. As it relates to the central nervous system, WNT signaling plays several roles as it relates to neurogenesis, synaptic formation, memory, and learning. Thus, dysfunction of this pathway is associated with multiple diseases and disorders, including several neurodegenerative disorders. Alzheimer's disease (AD) is characterized by several pathologies, synaptic dysfunction, and cognitive decline. In this review, we will discuss the various epidemiological, clinical, and animal studies that demonstrate a precise link between aberrant WNT signaling and AD-associated pathologies. In turn, we will discuss the manner in which WNT signaling influences multiple molecular, biochemical, and cellular pathways upstream of these end-point pathologies. Finally, we will discuss how merging tools and technologies can be used to generate next generation cellular models to dissect the relationship between WNT signaling and AD.
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Affiliation(s)
| | - David A. Brafman
- School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ 85287, USA
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18
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Hebisch M, Klostermeier S, Wolf K, Boccaccini AR, Wolf SE, Tanzi RE, Kim DY. The Impact of the Cellular Environment and Aging on Modeling Alzheimer's Disease in 3D Cell Culture Models. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2205037. [PMID: 36642841 PMCID: PMC10015857 DOI: 10.1002/advs.202205037] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 11/29/2022] [Indexed: 06/13/2023]
Abstract
Creating a cellular model of Alzheimer's disease (AD) that accurately recapitulates disease pathology has been a longstanding challenge. Recent studies showed that human AD neural cells, integrated into three-dimensional (3D) hydrogel matrix, display key features of AD neuropathology. Like in the human brain, the extracellular matrix (ECM) plays a critical role in determining the rate of neuropathogenesis in hydrogel-based 3D cellular models. Aging, the greatest risk factor for AD, significantly alters brain ECM properties. Therefore, it is important to understand how age-associated changes in ECM affect accumulation of pathogenic molecules, neuroinflammation, and neurodegeneration in AD patients and in vitro models. In this review, mechanistic hypotheses is presented to address the impact of the ECM properties and their changes with aging on AD and AD-related dementias. Altered ECM characteristics in aged brains, including matrix stiffness, pore size, and composition, will contribute to disease pathogenesis by modulating the accumulation, propagation, and spreading of pathogenic molecules of AD. Emerging hydrogel-based disease models with differing ECM properties provide an exciting opportunity to study the impact of brain ECM aging on AD pathogenesis, providing novel mechanistic insights. Understanding the role of ECM aging in AD pathogenesis should also improve modeling AD in 3D hydrogel systems.
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Affiliation(s)
- Matthias Hebisch
- Genetics and Aging Research UnitMcCance Center for Brain health, MassGeneral Institute for Neurodegenerative DiseaseMassachusetts General HospitalHarvard Medical SchoolCharlestownMA02129USA
| | - Stefanie Klostermeier
- Institute of Medical PhysicsFriedrich‐Alexander Universität Erlangen‐Nürnberg91052ErlangenGermany
- Max‐Planck‐Zentrum für Physik und Medizin91054ErlangenGermany
| | - Katharina Wolf
- Department of Medicine 1Friedrich‐Alexander‐Universität Erlangen‐Nürnberg91054ErlangenGermany
| | - Aldo R. Boccaccini
- Institute of BiomaterialsDepartment of Materials Science and EngineeringFriedrich‐Alexander‐Universität Erlangen‐Nürnberg91058ErlangenGermany
| | - Stephan E. Wolf
- Institute of Glass and CeramicsDepartment of Materials Science and EngineeringFriedrich‐Alexander‐Universität Erlangen‐Nürnberg91058ErlangenGermany
| | - Rudolph E. Tanzi
- Genetics and Aging Research UnitMcCance Center for Brain health, MassGeneral Institute for Neurodegenerative DiseaseMassachusetts General HospitalHarvard Medical SchoolCharlestownMA02129USA
| | - Doo Yeon Kim
- Genetics and Aging Research UnitMcCance Center for Brain health, MassGeneral Institute for Neurodegenerative DiseaseMassachusetts General HospitalHarvard Medical SchoolCharlestownMA02129USA
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19
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Sreenivasamurthy S, Laul M, Zhao N, Kim T, Zhu D. Current progress of cerebral organoids for modeling Alzheimer's disease origins and mechanisms. Bioeng Transl Med 2023; 8:e10378. [PMID: 36925717 PMCID: PMC10013781 DOI: 10.1002/btm2.10378] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 07/06/2022] [Accepted: 07/16/2022] [Indexed: 11/06/2022] Open
Abstract
Alzheimer's disease (AD) is a progressive, neurodegenerative disease that has emerged as a leading risk factor for dementia associated with increasing age. Two-dimensional (2D) cell culture and animal models, which have been used to analyze AD pathology and search for effective treatments for decades, have significantly contributed to our understanding of the mechanism of AD. Despite their successes, 2D and animal models can only capture a fraction of AD mechanisms due to their inability to recapitulate human brain-specific tissue structure, function, and cellular diversity. Recently, the emergence of three-dimensional (3D) cerebral organoids using tissue engineering and induced pluripotent stem cell technology has paved the way to develop models that resemble features of human brain tissue more accurately in comparison to prior models. In this review, we focus on summarizing key research strategies for engineering in vitro 3D human brain-specific models, major discoveries from using AD cerebral organoids, and its future perspectives.
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Affiliation(s)
- Sai Sreenivasamurthy
- Department of Biomedical EngineeringStony Brook UniversityStony BrookNew YorkUSA
| | - Mahek Laul
- Department of Biomedical EngineeringStony Brook UniversityStony BrookNew YorkUSA
| | - Nan Zhao
- Institute for NanobiotechnologyJohns Hopkins UniversityBaltimoreMarylandUSA
| | - Tiffany Kim
- Department of Biomedical EngineeringStony Brook UniversityStony BrookNew YorkUSA
| | - Donghui Zhu
- Department of Biomedical EngineeringStony Brook UniversityStony BrookNew YorkUSA
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20
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Kang YJ, Xue Y, Shin JH, Cho H. Human mini-brains for reconstituting central nervous system disorders. LAB ON A CHIP 2023; 23:964-981. [PMID: 36644973 DOI: 10.1039/d2lc00897a] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
Neurological disorders in the central nervous system (CNS) are progressive and irreversible diseases leading to devastating impacts on patients' life as they cause cognitive impairment, dementia, and even loss of essential body functions. The development of effective medicines curing CNS disorders is, however, one of the most ambitious challenges due to the extremely complex functions and structures of the human brain. In this regard, there are unmet needs to develop simplified but physiopathologically-relevant brain models. Recent advances in the microfluidic techniques allow multicellular culture forming miniaturized 3D human brains by aligning parts of brain regions with specific cells serving suitable functions. In this review, we overview designs and strategies of microfluidics-based human mini-brains for reconstituting CNS disorders, particularly Alzheimer's disease (AD), Parkinson's disease (PD), traumatic brain injury (TBI), vascular dementia (VD), and environmental risk factor-driven dementia (ERFD). Afterward, the applications of the mini-brains in the area of medical science are introduced in terms of the clarification of pathogenic mechanisms and identification of promising biomarkers. We also present expanded model systems ranging from the CNS to CNS-connecting organ axes to study the entry pathways of pathological risk factors into the brain. Lastly, the advantages and potential challenges of current model systems are addressed with future perspectives.
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Affiliation(s)
- You Jung Kang
- Institute of Quantum Biophysics, Sungkyunkwan University, Suwon, Republic of Korea.
- Department of Biophysics, Sungkyunkwan University, Suwon, Republic of Korea
| | - Yingqi Xue
- Institute of Quantum Biophysics, Sungkyunkwan University, Suwon, Republic of Korea.
- Department of Biophysics, Sungkyunkwan University, Suwon, Republic of Korea
| | - Jae Hee Shin
- Institute of Quantum Biophysics, Sungkyunkwan University, Suwon, Republic of Korea.
- Department of Biophysics, Sungkyunkwan University, Suwon, Republic of Korea
| | - Hansang Cho
- Institute of Quantum Biophysics, Sungkyunkwan University, Suwon, Republic of Korea.
- Department of Biophysics, Sungkyunkwan University, Suwon, Republic of Korea
- Department of Intelligent Precision Healthcare Convergence, Sungkyunkwan University, Suwon, Republic of Korea
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21
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Tevlek A, Kecili S, Ozcelik OS, Kulah H, Tekin HC. Spheroid Engineering in Microfluidic Devices. ACS OMEGA 2023; 8:3630-3649. [PMID: 36743071 PMCID: PMC9893254 DOI: 10.1021/acsomega.2c06052] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 12/12/2022] [Indexed: 05/27/2023]
Abstract
Two-dimensional (2D) cell culture techniques are commonly employed to investigate biophysical and biochemical cellular responses. However, these culture methods, having monolayer cells, lack cell-cell and cell-extracellular matrix interactions, mimicking the cell microenvironment and multicellular organization. Three-dimensional (3D) cell culture methods enable equal transportation of nutrients, gas, and growth factors among cells and their microenvironment. Therefore, 3D cultures show similar cell proliferation, apoptosis, and differentiation properties to in vivo. A spheroid is defined as self-assembled 3D cell aggregates, and it closely mimics a cell microenvironment in vitro thanks to cell-cell/matrix interactions, which enables its use in several important applications in medical and clinical research. To fabricate a spheroid, conventional methods such as liquid overlay, hanging drop, and so forth are available. However, these labor-intensive methods result in low-throughput fabrication and uncontrollable spheroid sizes. On the other hand, microfluidic methods enable inexpensive and rapid fabrication of spheroids with high precision. Furthermore, fabricated spheroids can also be cultured in microfluidic devices for controllable cell perfusion, simulation of fluid shear effects, and mimicking of the microenvironment-like in vivo conditions. This review focuses on recent microfluidic spheroid fabrication techniques and also organ-on-a-chip applications of spheroids, which are used in different disease modeling and drug development studies.
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Affiliation(s)
- Atakan Tevlek
- METU
MEMS Research and Application Center, Ankara 06800, Turkey
| | - Seren Kecili
- The
Department of Bioengineering, Izmir Institute
of Technology, Urla, Izmir 35430, Turkey
| | - Ozge S. Ozcelik
- The
Department of Bioengineering, Izmir Institute
of Technology, Urla, Izmir 35430, Turkey
| | - Haluk Kulah
- METU
MEMS Research and Application Center, Ankara 06800, Turkey
- The
Department of Electrical and Electronics Engineering, Middle East Technical University, Ankara 06800, Turkey
| | - H. Cumhur Tekin
- METU
MEMS Research and Application Center, Ankara 06800, Turkey
- The
Department of Bioengineering, Izmir Institute
of Technology, Urla, Izmir 35430, Turkey
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22
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Park H, Kim J, Ryou C. A three-dimensional spheroid co-culture system of neurons and astrocytes derived from Alzheimer's disease patients for drug efficacy testing. Cell Prolif 2023:e13399. [PMID: 36628615 DOI: 10.1111/cpr.13399] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 12/30/2022] [Accepted: 12/30/2022] [Indexed: 01/12/2023] Open
Abstract
Cell culture systems derived from the progenitor cells of human patients have many advantages over animal models for therapeutic drug testing and studies of disease pathogenesis. Here we describe a three-dimensional (3D) spheroid co-culture system of neurons and astrocytes derived from induced pluripotent stem cells-neural precursor cells (iPSCs-NPCs) of Alzheimer's disease (AD) patients or healthy individuals that can provide information on drug efficacy unobtainable by 2D co-culture or monoculture approaches. iPSCs-NPCs of healthy controls or AD patients were seeded onto 96-well U-bottom plates and incubated with neuronal differentiation medium for one week and with astrocytic medium for two weeks to replicate the temporal order of cell maturation during brain development. These 3D spheroid models expressed marker proteins for mature neurons and astrocytes. In particular, patient-derived spheroids showed beta-amyloid (Aβ) accumulation as revealed by thioflavin T (ThT) staining and ELISA. Aggregation of Aβ induced caspase activation and cell death, while the neuroprotectants nordihydroguaiaretic acid (NDGA) and curcumin (CU) reduced the levels of both ThT and caspase staining. Taken together, these results demonstrate the feasibility of our 3D spheroids combined with ThT and caspase staining as a patient-based anti-AD drug screening platform.
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Affiliation(s)
- HyunJung Park
- Department of Pharmacy, College of Pharmacy, and Institute of Pharmaceutical Science & Technology, Hanyang University, Ansan, Gyeonggi-do, Republic of Korea
| | - Jaehyeon Kim
- Department of Pharmacy, College of Pharmacy, and Institute of Pharmaceutical Science & Technology, Hanyang University, Ansan, Gyeonggi-do, Republic of Korea
| | - Chongsuk Ryou
- Department of Pharmacy, College of Pharmacy, and Institute of Pharmaceutical Science & Technology, Hanyang University, Ansan, Gyeonggi-do, Republic of Korea
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23
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In Vitro 3D Modeling of Neurodegenerative Diseases. BIOENGINEERING (BASEL, SWITZERLAND) 2023; 10:bioengineering10010093. [PMID: 36671665 PMCID: PMC9855033 DOI: 10.3390/bioengineering10010093] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 12/29/2022] [Accepted: 01/05/2023] [Indexed: 01/13/2023]
Abstract
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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24
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Halonen SK. Use of in vitro derived human neuronal models to study host-parasite interactions of Toxoplasma gondii in neurons and neuropathogenesis of chronic toxoplasmosis. Front Cell Infect Microbiol 2023; 13:1129451. [PMID: 36968101 PMCID: PMC10031036 DOI: 10.3389/fcimb.2023.1129451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 02/14/2023] [Indexed: 03/29/2023] Open
Abstract
Toxoplasma gondii infects approximately one-third of the world's population resulting in a chronic infection with the parasite located in cysts in neurons in the brain. In most immunocompetent hosts the chronic infection is asymptomatic, but several studies have found correlations between Toxoplasma seropositivity and neuropsychiatric disorders, including Schizophrenia, and some other neurological disorders. Host-parasite interactions of bradyzoites in cysts in neurons is not well understood due in part to the lack of suitable in vitro human neuronal models. The advent of stem cell technologies in which human neurons can be derived in vitro from human induced pluripotent stem cells (hiPSCs) or direct conversion of somatic cells generating induced neurons (iNs), affords the opportunity to develop in vitro human neuronal culture systems to advance the understanding of T. gondii in human neurons. Human neurons derived from hiPSCs or iNs, generate pure human neuron monolayers that express differentiated neuronal characteristics. hiPSCs also generate 3D neuronal models that better recapitulate the cytoarchitecture of the human brain. In this review, an overview of iPSC-derived neurons and iN protocols leading to 2D human neuron cultures and hiPSC-derived 3D cerebral organoids will be given. The potential applications of these 2D and 3D human neuronal models to address questions about host-parasite interactions of T. gondii in neurons and the parasite in the CNS, will be discussed. These human neuronal in vitro models hold the promise to advance the understanding of T. gondii in human neurons and to improve the understanding of neuropathogenesis of chronic toxoplasmosis.
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25
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Prasannan P, Siney E, Chatterjee S, Johnston D, Shah M, Mudher A, Willaime-Morawek S. A 3D-induced pluripotent stem cell-derived human neural culture model to study certain molecular and biochemical aspects of Alzheimer's disease. IN VITRO MODELS 2022; 1:447-462. [PMID: 39872613 PMCID: PMC11756488 DOI: 10.1007/s44164-022-00038-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 10/14/2022] [Accepted: 10/20/2022] [Indexed: 01/30/2025]
Abstract
Purpose Alzheimer's disease (AD) early pathology needs better understanding and models. Here, we describe a human induced pluripotent stem cells (iPSCs)-derived 3D neural culture model to study certain aspects of AD biochemistry and pathology. Method iPSCs derived from controls and AD patients with Presenilin1 mutations were cultured in a 3D platform with a similar microenvironment to the brain, to differentiate into neurons and astrocytes and self-organise into 3D structures by 3 weeks of differentiation in vitro. Results Cells express astrocytic (GFAP), neuronal (β3-Tubulin, MAP2), glutamatergic (VGLUT1), GABAergic (GAD65/67), pre-synaptic (Synapsin1) markers and a low level of neural progenitor cell (Nestin) marker after 6 and 12 weeks of differentiation in 3D. The foetal 3R Tau isoforms and adult 4R Tau isoforms were detected at 6 weeks post differentiation, showing advanced neuronal maturity. In the 3D AD cells, total and insoluble Tau levels were higher than in 3D control cells. Conclusion Our data indicates that this model may recapitulate the early biochemical and pathological disease features and can be a relevant platform for studying early cellular and biochemical changes and the identification of drug targets. Supplementary Information The online version contains supplementary material available at 10.1007/s44164-022-00038-5.
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Affiliation(s)
| | - Elodie Siney
- Faculty of Medicine, University of Southampton, Southampton, UK
| | | | - David Johnston
- Faculty of Medicine, University of Southampton, Southampton, UK
| | - Mohammad Shah
- Faculty of Medicine, University of Southampton, Southampton, UK
| | - Amrit Mudher
- School of Biological Sciences, University of Southampton, Southampton, UK
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26
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Chen H, Jin X, Li T, Ye Z. Brain organoids: Establishment and application. Front Cell Dev Biol 2022; 10:1029873. [PMID: 36506083 PMCID: PMC9726712 DOI: 10.3389/fcell.2022.1029873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 11/10/2022] [Indexed: 11/24/2022] Open
Abstract
Brain organoids are produced by the differentiation of pluripotent stem cells under three-dimensional culture conditions by adding neurodevelopment-related regulatory signals. They are similar to the cell composition and anatomical structure of the brain, and can reflect the developmental process of the brain, as well as their physiology, pathology, and pharmacology. Brain organoids are good models to study human brain development and brain-related diseases in vitro. Here, we mainly focus on the construction of brain organoids and review the application of brain organoids in disease modelingand drug screening.
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Affiliation(s)
- Hao Chen
- Department of Neurovascular Surgery, First Hospital, Jilin University, Changchun, China
| | - Xin Jin
- Department of Oncology and Hematology, Second Hospital, Jilin University, Changchun, China
| | - Tie Li
- Department of Rheumatology, First Hospital, Jilin University, Changchun, China
| | - Zhuang Ye
- Department of Rheumatology, First Hospital, Jilin University, Changchun, China,*Correspondence: Zhuang Ye,
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27
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Alzheimer's Disease: Treatment Strategies and Their Limitations. Int J Mol Sci 2022; 23:ijms232213954. [PMID: 36430432 PMCID: PMC9697769 DOI: 10.3390/ijms232213954] [Citation(s) in RCA: 212] [Impact Index Per Article: 70.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/08/2022] [Accepted: 11/09/2022] [Indexed: 11/16/2022] Open
Abstract
Alzheimer's disease (AD) is the most frequent case of neurodegenerative disease and is becoming a major public health problem all over the world. Many therapeutic strategies have been explored for several decades; however, there is still no curative treatment, and the priority remains prevention. In this review, we present an update on the clinical and physiological phase of the AD spectrum, modifiable and non-modifiable risk factors for AD treatment with a focus on prevention strategies, then research models used in AD, followed by a discussion of treatment limitations. The prevention methods can significantly slow AD evolution and are currently the best strategy possible before the advanced stages of the disease. Indeed, current drug treatments have only symptomatic effects, and disease-modifying treatments are not yet available. Drug delivery to the central nervous system remains a complex process and represents a challenge for developing therapeutic and preventive strategies. Studies are underway to test new techniques to facilitate the bioavailability of molecules to the brain. After a deep study of the literature, we find the use of soft nanoparticles, in particular nanoliposomes and exosomes, as an innovative approach for preventive and therapeutic strategies in reducing the risk of AD and solving problems of brain bioavailability. Studies show the promising role of nanoliposomes and exosomes as smart drug delivery systems able to penetrate the blood-brain barrier and target brain tissues. Finally, the different drug administration techniques for neurological disorders are discussed. One of the promising therapeutic methods is the intranasal administration strategy which should be used for preclinical and clinical studies of neurodegenerative diseases.
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28
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High throughput 3D gel-based neural organotypic model for cellular assays using fluorescence biosensors. Commun Biol 2022; 5:1236. [PMID: 36371462 PMCID: PMC9653447 DOI: 10.1038/s42003-022-04177-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 10/27/2022] [Indexed: 11/13/2022] Open
Abstract
Three-dimensional (3D) organotypic models that capture native-like physiological features of tissues are being pursued as clinically predictive assays for therapeutics development. A range of these models are being developed to mimic brain morphology, physiology, and pathology of neurological diseases. Biofabrication of 3D gel-based cellular systems is emerging as a versatile technology to produce spatially and cell-type tailored, physiologically complex and native-like tissue models. Here we produce 3D fibrin gel-based functional neural co-culture models with human-iPSC differentiated dopaminergic or glutamatergic neurons and astrocytes. We further introduce genetically encoded fluorescence biosensors and optogenetics activation for real time functional measurements of intracellular calcium and levels of dopamine and glutamate neurotransmitters, in a high-throughput compatible plate format. We use pharmacological perturbations to demonstrate that the drug responses of 3D gel-based neural models are like those expected from in-vivo data, and in some cases, in contrast to those observed in the equivalent 2D neural models. Fibrin gel-based 3D co-culture models with human-iPSC differentiated dopaminergic or glutamatergic neurons and astrocytes are shown to be functional using biosensors and can be scaled up for high-throughput assays.
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29
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Fabrication of Cell Spheroids for 3D Cell Culture and Biomedical Applications. BIOCHIP JOURNAL 2022. [DOI: 10.1007/s13206-022-00086-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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30
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Rickner HD, Jiang L, Hong R, O'Neill NK, Mojica CA, Snyder BJ, Zhang L, Shaw D, Medalla M, Wolozin B, Cheng CS. Single cell transcriptomic profiling of a neuron-astrocyte assembloid tauopathy model. Nat Commun 2022; 13:6275. [PMID: 36271092 PMCID: PMC9587045 DOI: 10.1038/s41467-022-34005-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 10/10/2022] [Indexed: 12/25/2022] Open
Abstract
The use of iPSC derived brain organoid models to study neurodegenerative disease has been hampered by a lack of systems that accurately and expeditiously recapitulate pathogenesis in the context of neuron-glial interactions. Here we report development of a system, termed AstTau, which propagates toxic human tau oligomers in iPSC derived neuron-astrocyte assembloids. The AstTau system develops much of the neuronal and astrocytic pathology observed in tauopathies including misfolded, phosphorylated, oligomeric, and fibrillar tau, strong neurodegeneration, and reactive astrogliosis. Single cell transcriptomic profiling combined with immunochemistry characterizes a model system that can more closely recapitulate late-stage changes in adult neurodegeneration. The transcriptomic studies demonstrate striking changes in neuroinflammatory and heat shock protein (HSP) chaperone systems in the disease process. Treatment with the HSP90 inhibitor PU-H71 is used to address the putative dysfunctional HSP chaperone system and produces a strong reduction of pathology and neurodegeneration, highlighting the potential of AstTau as a rapid and reproducible tool for drug discovery.
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Affiliation(s)
| | - Lulu Jiang
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, 02118, USA
| | - Rui Hong
- Program in Bioinformatics, Boston University, Boston, MA, 02215, USA
| | | | - Chromewell A Mojica
- Department of Anatomy & Neurobiology, Boston University School of Medicine, Boston, MA, 02118, USA
| | - Benjamin J Snyder
- Department of Anatomy & Neurobiology, Boston University School of Medicine, Boston, MA, 02118, USA
| | - Lushuang Zhang
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, 02118, USA
| | - Dipan Shaw
- Informatics Group, J. Craig Venter Institute, La Jolla, CA, 92037, USA
| | - Maria Medalla
- Department of Anatomy & Neurobiology, Boston University School of Medicine, Boston, MA, 02118, USA
- Department of Neurology, Boston University School of Medicine, Boston, MA, 02118, USA
| | - Benjamin Wolozin
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, 02118, USA.
- Department of Neurology, Boston University School of Medicine, Boston, MA, 02118, USA.
- Center for Systems Neuroscience, Boston University, Boston, MA, 02118, USA.
| | - Christine S Cheng
- Department of Biology, Boston University, Boston, MA, 02215, USA.
- Program in Bioinformatics, Boston University, Boston, MA, 02215, USA.
- Informatics Group, J. Craig Venter Institute, La Jolla, CA, 92037, USA.
- Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093, USA.
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31
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Damianidou E, Mouratidou L, Kyrousi C. Research models of neurodevelopmental disorders: The right model in the right place. Front Neurosci 2022; 16:1031075. [PMID: 36340790 PMCID: PMC9630472 DOI: 10.3389/fnins.2022.1031075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 10/07/2022] [Indexed: 11/25/2022] Open
Abstract
Neurodevelopmental disorders (NDDs) are a heterogeneous group of impairments that affect the development of the central nervous system leading to abnormal brain function. NDDs affect a great percentage of the population worldwide, imposing a high societal and economic burden and thus, interest in this field has widely grown in recent years. Nevertheless, the complexity of human brain development and function as well as the limitations regarding human tissue usage make their modeling challenging. Animal models play a central role in the investigation of the implicated molecular and cellular mechanisms, however many of them display key differences regarding human phenotype and in many cases, they partially or completely fail to recapitulate them. Although in vitro two-dimensional (2D) human-specific models have been highly used to address some of these limitations, they lack crucial features such as complexity and heterogeneity. In this review, we will discuss the advantages, limitations and future applications of in vivo and in vitro models that are used today to model NDDs. Additionally, we will describe the recent development of 3-dimensional brain (3D) organoids which offer a promising approach as human-specific in vitro models to decipher these complex disorders.
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Affiliation(s)
- Eleni Damianidou
- University Mental Health, Neurosciences and Precision Medicine Research Institute “Costas Stefanis”, Athens, Greece
| | - Lidia Mouratidou
- University Mental Health, Neurosciences and Precision Medicine Research Institute “Costas Stefanis”, Athens, Greece
- First Department of Psychiatry, Medical School, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Christina Kyrousi
- University Mental Health, Neurosciences and Precision Medicine Research Institute “Costas Stefanis”, Athens, Greece
- First Department of Psychiatry, Medical School, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
- *Correspondence: Christina Kyrousi,
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32
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Srivastava R, Li A, Datta T, Jha NK, Talukder S, Jha SK, Chen ZS. Advances in stromal cell therapy for management of Alzheimer’s disease. Front Pharmacol 2022; 13:955401. [PMID: 36267273 PMCID: PMC9576849 DOI: 10.3389/fphar.2022.955401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 09/08/2022] [Indexed: 11/13/2022] Open
Abstract
Deposition of misfolded proteins and synaptic failure affects the brain in Alzheimer’s disease (AD). Its progression results in amnesia and cognitive impairment. Absence of treatment is due to excessive loss of neurons in the patients and the delayed effects of drugs. The enhanced pluripotency, proliferation, differentiation, and recombination characteristics of stromal cells into nerve cells and glial cells present them as a potential treatment for AD. Successful evidence of action in animal models along with positive results in preclinical studies further encourage its utilization for AD treatment. With regard to humans, cell replacement therapy involving mesenchymal stromal cells, induced-pluripotent stromal cells, human embryonic stromal cells, and neural stems show promising results in clinical trials. However, further research is required prior to its use as stromal cell therapy in AD related disorders. The current review deals with the mechanism of development of anomalies such as Alzheimer’s and the prospective applications of stromal cells for treatment.
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Affiliation(s)
- Rashi Srivastava
- Chemical and Biochemical Engineering, Indian Institute of Technology, Patna, India
| | - Aidong Li
- Department of Rehabilitation, The Second People’s Hospital of Shenzhen, Shenzhen, China
| | - Tirtharaj Datta
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, India
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, India
| | - Salehikram Talukder
- Institute for Biotechnology, St. John’s University, New York City, NY, United States
| | - Saurabh Kumar Jha
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, India
- Department of Biotechnology, School of Applied and Life Sciences, Uttaranchal University, Dehradun, India
- Department of Biotechnology Engineering and Food Technology, Chandigarh University, Mohali, India
- *Correspondence: Saurabh Kumar Jha, ; Zhe-Sheng Chen,
| | - Zhe-Sheng Chen
- Institute for Biotechnology, St. John’s University, New York City, NY, United States
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, New York City, NY, United States
- *Correspondence: Saurabh Kumar Jha, ; Zhe-Sheng Chen,
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33
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Alghamdi A, Birch DJS, Vyshemirsky V, Rolinski OJ. Impact of the Flavonoid Quercetin on β-Amyloid Aggregation Revealed by Intrinsic Fluorescence. J Phys Chem B 2022; 126:7229-7237. [PMID: 36121408 PMCID: PMC9527748 DOI: 10.1021/acs.jpcb.2c02763] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
We report the effects of quercetin, a flavonoid present in the human diet, on early stage beta-amyloid (Aβ) aggregation, a seminal event in Alzheimer's disease. Molecular level changes in Aβ arrangements are monitored by time-resolved emission spectral (TRES) measurements of the fluorescence of Aβ's single tyrosine intrinsic fluorophore (Tyr). The results suggest that quercetin binds β-amyloid oligomers at early stages of their aggregation, which leads to the formation of modified oligomers and hinders the creation of β-sheet structures, potentially preventing the onset of Alzheimer's disease.
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Affiliation(s)
- Abeer Alghamdi
- Photophysics Group, Centre for Molecular Nanometrology, Department of Physics, Scottish Universities Physics Alliance, University of Strathclyde, 107 Rottenrow East, Glasgow G4 0NG, United Kingdom
| | - David J S Birch
- Photophysics Group, Centre for Molecular Nanometrology, Department of Physics, Scottish Universities Physics Alliance, University of Strathclyde, 107 Rottenrow East, Glasgow G4 0NG, United Kingdom
| | - Vladislav Vyshemirsky
- School of Mathematics and Statistics, University of Glasgow, Glasgow G12 8QQ, United Kingdom
| | - Olaf J Rolinski
- Photophysics Group, Centre for Molecular Nanometrology, Department of Physics, Scottish Universities Physics Alliance, University of Strathclyde, 107 Rottenrow East, Glasgow G4 0NG, United Kingdom
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34
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Glasauer SMK, Goderie SK, Rauch JN, Guzman E, Audouard M, Bertucci T, Joy S, Rommelfanger E, Luna G, Keane-Rivera E, Lotz S, Borden S, Armando AM, Quehenberger O, Temple S, Kosik KS. Human tau mutations in cerebral organoids induce a progressive dyshomeostasis of cholesterol. Stem Cell Reports 2022; 17:2127-2140. [PMID: 35985329 PMCID: PMC9481908 DOI: 10.1016/j.stemcr.2022.07.011] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/18/2022] [Accepted: 07/19/2022] [Indexed: 11/26/2022] Open
Abstract
Mutations in the MAPT gene that encodes tau lead to frontotemporal dementia (FTD) with pathology evident in both cerebral neurons and glia. Human cerebral organoids (hCOs) from individuals harboring pathogenic tau mutations can reveal the earliest downstream effects on molecular pathways within a developmental context, generating interacting neurons and glia. We found that in hCOs carrying the V337M and R406W tau mutations, the cholesterol biosynthesis pathway in astrocytes was the top upregulated gene set compared with isogenic controls by single-cell RNA sequencing (scRNA-seq). The 15 upregulated genes included HMGCR, ACAT2, STARD4, LDLR, and SREBF2. This result was confirmed in a homozygous R406W mutant cell line by immunostaining and sterol measurements. Cholesterol abundance in the brain is tightly regulated by efflux and cholesterol biosynthetic enzyme levels in astrocytes, and dysregulation can cause aberrant phosphorylation of tau. Our findings suggest that cholesterol dyshomeostasis is an early event in the etiology of neurodegeneration caused by tau mutations.
Cerebral organoid models of tauopathy caused by MAPT mutations Upregulated cholesterol and fatty acid biosynthesis genes in MAPT mutant astrocytes Elevation of cholesterol and its precursors in MAPT mutant cerebral organoids
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Affiliation(s)
- Stella M K Glasauer
- Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA
| | | | - Jennifer N Rauch
- Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA
| | - Elmer Guzman
- Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA
| | - Morgane Audouard
- Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA
| | | | - Shona Joy
- Neural Stem Cell Institute, Rensselaer, NY 12144, USA
| | - Emma Rommelfanger
- Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA
| | - Gabriel Luna
- Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA
| | - Erica Keane-Rivera
- Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA
| | - Steven Lotz
- Neural Stem Cell Institute, Rensselaer, NY 12144, USA
| | - Susan Borden
- Neural Stem Cell Institute, Rensselaer, NY 12144, USA
| | - Aaron M Armando
- Department of Pharmacology, University of California, San Diego, San Diego, CA 92093, USA
| | - Oswald Quehenberger
- Department of Pharmacology, University of California, San Diego, San Diego, CA 92093, USA
| | - Sally Temple
- Neural Stem Cell Institute, Rensselaer, NY 12144, USA.
| | - Kenneth S Kosik
- Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.
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35
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Yoon J, Kim HW, Shin M, Lim J, Lee JY, Lee SN, Choi JW. 3D Neural Network Composed of Neurospheroid and Bionanohybrid on Microelectrode Array to Realize the Spatial Input Signal Recognition in Neurospheroid. SMALL METHODS 2022; 6:e2200127. [PMID: 35595685 DOI: 10.1002/smtd.202200127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 05/03/2022] [Indexed: 06/15/2023]
Abstract
There have been several studies for demonstration of 2D neural network using living cells or organic/inorganic molecules, but to date, there is no report of development of a 3D neural network in vitro. Based on developed bionanohybrid composed of protein, DNA, molybdenum disulfide nanoparticles, and peptides for controlling electrophysiological states of living cells, here, the in vitro 3D neural network composed of the bionanohybrid, 3D neurospheroid and the microelectrode array (MEA) is developed. After production of the 3D neurospheroid derived from human neural stem cells, the bionanohybrid developed on the MEA successfully semi-penetrates the neurites of the 3D neurospheroid and forms the 3D neural network. The developed 3D neural network successfully exhibited the electrophysiological output signals of the 3D neurospheroid by transmitting the input signal applied by the bionanohybrid. Moreover, by using the selectively immobilized bionanohybrid on the MEA, the spatial input signal recognition in the neurospheroid of 3D neural network is realized for the first time. This newly developed in vitro 3D neural network provides a promising strategy to be applied in brain-on-a-chip, brain disease-related drug efficacy evaluation, bioelectronics, and bioelectronic medicine.
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Affiliation(s)
- Jinho Yoon
- Department of Chemical & Biomolecular Engineering, Sogang University, Seoul, 04107, Republic of Korea
- Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 123 Bevier Road, Piscataway, NJ, 08854, USA
| | - Hyun-Woong Kim
- Department of Chemical & Biomolecular Engineering, Sogang University, Seoul, 04107, Republic of Korea
| | - Minkyu Shin
- Department of Chemical & Biomolecular Engineering, Sogang University, Seoul, 04107, Republic of Korea
| | - Joungpyo Lim
- Department of Chemical & Biomolecular Engineering, Sogang University, Seoul, 04107, Republic of Korea
| | - Ji-Young Lee
- Department of Chemical & Biomolecular Engineering, Sogang University, Seoul, 04107, Republic of Korea
| | - Sang-Nam Lee
- Uniance Gene Inc., Seoul, 04107, Republic of Korea
| | - Jeong-Woo Choi
- Department of Chemical & Biomolecular Engineering, Sogang University, Seoul, 04107, Republic of Korea
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36
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Van Breedam E, Ponsaerts P. Promising Strategies for the Development of Advanced In Vitro Models with High Predictive Power in Ischaemic Stroke Research. Int J Mol Sci 2022; 23:ijms23137140. [PMID: 35806146 PMCID: PMC9266337 DOI: 10.3390/ijms23137140] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 06/21/2022] [Accepted: 06/24/2022] [Indexed: 11/16/2022] Open
Abstract
Although stroke is one of the world’s leading causes of death and disability, and more than a thousand candidate neuroprotective drugs have been proposed based on extensive in vitro and animal-based research, an effective neuroprotective/restorative therapy for ischaemic stroke patients is still missing. In particular, the high attrition rate of neuroprotective compounds in clinical studies should make us question the ability of in vitro models currently used for ischaemic stroke research to recapitulate human ischaemic responses with sufficient fidelity. The ischaemic stroke field would greatly benefit from the implementation of more complex in vitro models with improved physiological relevance, next to traditional in vitro and in vivo models in preclinical studies, to more accurately predict clinical outcomes. In this review, we discuss current in vitro models used in ischaemic stroke research and describe the main factors determining the predictive value of in vitro models for modelling human ischaemic stroke. In light of this, human-based 3D models consisting of multiple cell types, either with or without the use of microfluidics technology, may better recapitulate human ischaemic responses and possess the potential to bridge the translational gap between animal-based in vitro and in vivo models, and human patients in clinical trials.
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37
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Tabibzadeh S. Repair, regeneration and rejuvenation require un-entangling pluripotency from senescence. Ageing Res Rev 2022; 80:101663. [PMID: 35690382 DOI: 10.1016/j.arr.2022.101663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 05/27/2022] [Accepted: 06/04/2022] [Indexed: 11/16/2022]
Abstract
There is a notion that pluripotency and senescence, represent two extremes of life of cells. Pluripotent cells display epigenetic youth, unlimited proliferative capacity and pluripotent differentiating potential whereas cells that reach the Hayflick limit, transit to senescence, undergo permanent inhibition of cell replication and create an aging tissue landscape. However, pluripotency and senescence appear to be intimately linked and are jointly generated in many different contexts such as during embryogenesis or formation of tissue spheroids, in stem cell niches, cancer, or by induction of a pluripotent state (induced pluripotency). Tissue damage and senescence provide signals that are critical to generation of a pluripotent state and, in turn, pluripotency, induces senescence. Thus, it follows, that precisely timed control of senescence is required for harnessing the full benefits of both senescence and its associated pluripotency during tissue regeneration or rejuvenation.
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Affiliation(s)
- Siamak Tabibzadeh
- Frontiers in Bioscience Research Institute in Aging and Cancer, 16471 Scientific Way, Irvine, CA 92618.
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38
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Melliou S, Sangster KT, Kao J, Zarrei M, Lam KHB, Howe J, Papaioannou MD, Tsang QPL, Borhani OA, Sajid RS, Bonnet C, Leheup B, Shannon P, Scherer SW, Stavropoulos DJ, Djuric U, Diamandis P. Regionally defined proteomic profiles of human cerebral tissue and organoids reveal conserved molecular modules of neurodevelopment. Cell Rep 2022; 39:110846. [PMID: 35613588 DOI: 10.1016/j.celrep.2022.110846] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 02/01/2022] [Accepted: 04/28/2022] [Indexed: 12/14/2022] Open
Abstract
Cerebral organoids have emerged as robust models for neurodevelopmental and pathological processes, as well as a powerful discovery platform for less-characterized neurobiological programs. Toward this prospect, we leverage mass-spectrometry-based proteomics to molecularly profile precursor and neuronal compartments of both human-derived organoids and mid-gestation fetal brain tissue to define overlapping programs. Our analysis includes recovery of precursor-enriched transcriptional regulatory proteins not found to be differentially expressed in previous transcriptomic datasets. To highlight the discovery potential of this resource, we show that RUVBL2 is preferentially expressed in the SOX2-positive compartment of organoids and that chemical inactivation leads to precursor cell displacement and apoptosis. To explore clinicopathological correlates of this cytoarchitectural disruption, we interrogate clinical datasets and identify rare de novo genetic variants involving RUVBL2 in patients with neurodevelopmental impairments. Together, our findings demonstrate how cell-type-specific profiling of organoids can help nominate previously unappreciated genes in neurodevelopment and disease.
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Affiliation(s)
- Sofia Melliou
- Princess Margaret Cancer Centre, 101 College Street, Toronto, ON M5G 1L7, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Kevin T Sangster
- Princess Margaret Cancer Centre, 101 College Street, Toronto, ON M5G 1L7, Canada
| | - Jennifer Kao
- Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Mehdi Zarrei
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - K H Brian Lam
- Princess Margaret Cancer Centre, 101 College Street, Toronto, ON M5G 1L7, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Jennifer Howe
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | | | - Queenie P L Tsang
- Princess Margaret Cancer Centre, 101 College Street, Toronto, ON M5G 1L7, Canada
| | - Okty Abbasi Borhani
- Princess Margaret Cancer Centre, 101 College Street, Toronto, ON M5G 1L7, Canada
| | - Rifat Shahriar Sajid
- Princess Margaret Cancer Centre, 101 College Street, Toronto, ON M5G 1L7, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Céline Bonnet
- Department of Clinical Genetics, Nancy University Hospital, Nancy, France
| | - Bruno Leheup
- Department of Clinical Genetics, Nancy University Hospital, Nancy, France
| | - Patrick Shannon
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada
| | - Stephen W Scherer
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics and McLaughlin Centre, University of Toronto, Toronto, ON M5G 1X5, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - Dimitri James Stavropoulos
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - Ugljesa Djuric
- Princess Margaret Cancer Centre, 101 College Street, Toronto, ON M5G 1L7, Canada
| | - Phedias Diamandis
- Princess Margaret Cancer Centre, 101 College Street, Toronto, ON M5G 1L7, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Laboratory Medicine Program, University Health Network, 200 Elizabeth Street, Toronto, ON M5G 2C4, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5S 1A8, Canada.
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39
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Rathore RS, R Ayyannan S, Mahto SK. Emerging three-dimensional neuronal culture assays for neurotherapeutics drug discovery. Expert Opin Drug Discov 2022; 17:619-628. [DOI: 10.1080/17460441.2022.2061458] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Rahul S Rathore
- Pharmaceutical Chemistry Research Laboratory II, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi-221005, UP, India
| | - Senthil R Ayyannan
- Pharmaceutical Chemistry Research Laboratory II, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi-221005, UP, India
| | - Sanjeev K Mahto
- Tissue Engineering and Biomicrofluidics Laboratory, School of Biomedical Engineering, Indian Institute of Technology (Banaras Hindu University), Varanasi-221005, UP, India
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40
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Ning S, Jorfi M, Patel SR, Kim DY, Tanzi RE. Neurotechnological Approaches to the Diagnosis and Treatment of Alzheimer’s Disease. Front Neurosci 2022; 16:854992. [PMID: 35401082 PMCID: PMC8989850 DOI: 10.3389/fnins.2022.854992] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 02/25/2022] [Indexed: 12/12/2022] Open
Abstract
Alzheimer’s disease (AD) is the most common cause of dementia in the elderly, clinically defined by progressive cognitive decline and pathologically, by brain atrophy, neuroinflammation, and accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles. Neurotechnological approaches, including optogenetics and deep brain stimulation, have exploded as new tools for not only the study of the brain but also for application in the treatment of neurological diseases. Here, we review the current state of AD therapeutics and recent advancements in both invasive and non-invasive neurotechnologies that can be used to ameliorate AD pathology, including neurostimulation via optogenetics, photobiomodulation, electrical stimulation, ultrasound stimulation, and magnetic neurostimulation, as well as nanotechnologies employing nanovectors, magnetic nanoparticles, and quantum dots. We also discuss the current challenges in developing these neurotechnological tools and the prospects for implementing them in the treatment of AD and other neurodegenerative diseases.
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Affiliation(s)
- Shen Ning
- Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
- Graduate Program for Neuroscience, Boston University School of Medicine, Boston, MA, United States
| | - Mehdi Jorfi
- Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
- Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
- *Correspondence: Mehdi Jorfi,
| | - Shaun R. Patel
- Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Doo Yeon Kim
- Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Rudolph E. Tanzi
- Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
- Rudolph E. Tanzi,
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41
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Nguyen HN. Generation of iPSC-Derived Brain Organoids for Drug Testing and Toxicological Evaluation. METHODS IN MOLECULAR BIOLOGY (CLIFTON, N.J.) 2022; 2474:93-105. [PMID: 35294759 DOI: 10.1007/978-1-0716-2213-1_10] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The road to discover novel therapeutics for mental and neurological disorders has been severely hampered by the lack of access to relevant testing platforms. Currently, roughly 0.1% of drugs that show promise in preclinical testing make it to Phase I clinical trials, and 90% of those drugs go on to fail FDA approval. One of the reasons responsible for this low success rate is that conventional two-dimensional (2D) cell culture models are not accurate enough predictors of how drugs will work in humans. Three-dimensional (3D) brain organoids differentiated from induced pluripotent stem cells (iPSCs) to resemble specific parts of the human brain, which include architecture composition and physiology, can provide an alternative system that may lead to breakthroughs in key areas of drug testing and toxicological evaluation. Having reliable and scalable iPSC-derived brain organoid models that can much more accurately predict human drug responses will significantly increase success rate in developing treatments for brain-related disorders.
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42
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Pelucchi S, Gardoni F, Di Luca M, Marcello E. Synaptic dysfunction in early phases of Alzheimer's Disease. HANDBOOK OF CLINICAL NEUROLOGY 2022; 184:417-438. [PMID: 35034752 DOI: 10.1016/b978-0-12-819410-2.00022-9] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The synapse is the locus of plasticity where short-term alterations in synaptic strength are converted to long-lasting memories. In addition to the presynaptic terminal and the postsynaptic compartment, a more holistic view of the synapse includes the astrocytes and the extracellular matrix to form a tetrapartite synapse. All these four elements contribute to synapse health and are crucial for synaptic plasticity events and, thereby, for learning and memory processes. Synaptic dysfunction is a common pathogenic trait of several brain disorders. In Alzheimer's Disease, the degeneration of synapses can be detected at the early stages of pathology progression before neuronal degeneration, supporting the hypothesis that synaptic failure is a major determinant of the disease. The synapse is the place where amyloid-β peptides are generated and is the target of the toxic amyloid-β oligomers. All the elements constituting the tetrapartite synapse are altered in Alzheimer's Disease and can synergistically contribute to synaptic dysfunction. Moreover, the two main hallmarks of Alzheimer's Disease, i.e., amyloid-β and tau, act in concert to cause synaptic deficits. Deciphering the mechanisms underlying synaptic dysfunction is relevant for the development of the next-generation therapeutic strategies aimed at modifying the disease progression.
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Affiliation(s)
- Silvia Pelucchi
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Fabrizio Gardoni
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Monica Di Luca
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Elena Marcello
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.
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43
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Youhanna S, Kemas AM, Preiss L, Zhou Y, Shen JX, Cakal SD, Paqualini FS, Goparaju SK, Shafagh RZ, Lind JU, Sellgren CM, Lauschke VM. Organotypic and Microphysiological Human Tissue Models for Drug Discovery and Development-Current State-of-the-Art and Future Perspectives. Pharmacol Rev 2022; 74:141-206. [PMID: 35017176 DOI: 10.1124/pharmrev.120.000238] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 10/12/2021] [Indexed: 12/11/2022] Open
Abstract
The number of successful drug development projects has been stagnant for decades despite major breakthroughs in chemistry, molecular biology, and genetics. Unreliable target identification and poor translatability of preclinical models have been identified as major causes of failure. To improve predictions of clinical efficacy and safety, interest has shifted to three-dimensional culture methods in which human cells can retain many physiologically and functionally relevant phenotypes for extended periods of time. Here, we review the state of the art of available organotypic culture techniques and critically review emerging models of human tissues with key importance for pharmacokinetics, pharmacodynamics, and toxicity. In addition, developments in bioprinting and microfluidic multiorgan cultures to emulate systemic drug disposition are summarized. We close by highlighting important trends regarding the fabrication of organotypic culture platforms and the choice of platform material to limit drug absorption and polymer leaching while supporting the phenotypic maintenance of cultured cells and allowing for scalable device fabrication. We conclude that organotypic and microphysiological human tissue models constitute promising systems to promote drug discovery and development by facilitating drug target identification and improving the preclinical evaluation of drug toxicity and pharmacokinetics. There is, however, a critical need for further validation, benchmarking, and consolidation efforts ideally conducted in intersectoral multicenter settings to accelerate acceptance of these novel models as reliable tools for translational pharmacology and toxicology. SIGNIFICANCE STATEMENT: Organotypic and microphysiological culture of human cells has emerged as a promising tool for preclinical drug discovery and development that might be able to narrow the translation gap. This review discusses recent technological and methodological advancements and the use of these systems for hit discovery and the evaluation of toxicity, clearance, and absorption of lead compounds.
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Affiliation(s)
- Sonia Youhanna
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (S.Y., A.M.K., L.P., Y.Z., J.X.S., S.K.G., R.Z.S., C.M.S., V.M.L.); Department of Drug Metabolism and Pharmacokinetics (DMPK), Merck KGaA, Darmstadt, Germany (L.P.); Department of Health Technology, Technical University of Denmark, Lyngby, Denmark (S.D.C., J.U.L.); Synthetic Physiology Laboratory, Department of Civil Engineering and Architecture, University of Pavia, Pavia, Italy (F.S.P.); Division of Micro- and Nanosystems, KTH Royal Institute of Technology, Stockholm, Sweden (Z.S.); and Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany (V.M.L.)
| | - Aurino M Kemas
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (S.Y., A.M.K., L.P., Y.Z., J.X.S., S.K.G., R.Z.S., C.M.S., V.M.L.); Department of Drug Metabolism and Pharmacokinetics (DMPK), Merck KGaA, Darmstadt, Germany (L.P.); Department of Health Technology, Technical University of Denmark, Lyngby, Denmark (S.D.C., J.U.L.); Synthetic Physiology Laboratory, Department of Civil Engineering and Architecture, University of Pavia, Pavia, Italy (F.S.P.); Division of Micro- and Nanosystems, KTH Royal Institute of Technology, Stockholm, Sweden (Z.S.); and Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany (V.M.L.)
| | - Lena Preiss
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (S.Y., A.M.K., L.P., Y.Z., J.X.S., S.K.G., R.Z.S., C.M.S., V.M.L.); Department of Drug Metabolism and Pharmacokinetics (DMPK), Merck KGaA, Darmstadt, Germany (L.P.); Department of Health Technology, Technical University of Denmark, Lyngby, Denmark (S.D.C., J.U.L.); Synthetic Physiology Laboratory, Department of Civil Engineering and Architecture, University of Pavia, Pavia, Italy (F.S.P.); Division of Micro- and Nanosystems, KTH Royal Institute of Technology, Stockholm, Sweden (Z.S.); and Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany (V.M.L.)
| | - Yitian Zhou
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (S.Y., A.M.K., L.P., Y.Z., J.X.S., S.K.G., R.Z.S., C.M.S., V.M.L.); Department of Drug Metabolism and Pharmacokinetics (DMPK), Merck KGaA, Darmstadt, Germany (L.P.); Department of Health Technology, Technical University of Denmark, Lyngby, Denmark (S.D.C., J.U.L.); Synthetic Physiology Laboratory, Department of Civil Engineering and Architecture, University of Pavia, Pavia, Italy (F.S.P.); Division of Micro- and Nanosystems, KTH Royal Institute of Technology, Stockholm, Sweden (Z.S.); and Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany (V.M.L.)
| | - Joanne X Shen
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (S.Y., A.M.K., L.P., Y.Z., J.X.S., S.K.G., R.Z.S., C.M.S., V.M.L.); Department of Drug Metabolism and Pharmacokinetics (DMPK), Merck KGaA, Darmstadt, Germany (L.P.); Department of Health Technology, Technical University of Denmark, Lyngby, Denmark (S.D.C., J.U.L.); Synthetic Physiology Laboratory, Department of Civil Engineering and Architecture, University of Pavia, Pavia, Italy (F.S.P.); Division of Micro- and Nanosystems, KTH Royal Institute of Technology, Stockholm, Sweden (Z.S.); and Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany (V.M.L.)
| | - Selgin D Cakal
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (S.Y., A.M.K., L.P., Y.Z., J.X.S., S.K.G., R.Z.S., C.M.S., V.M.L.); Department of Drug Metabolism and Pharmacokinetics (DMPK), Merck KGaA, Darmstadt, Germany (L.P.); Department of Health Technology, Technical University of Denmark, Lyngby, Denmark (S.D.C., J.U.L.); Synthetic Physiology Laboratory, Department of Civil Engineering and Architecture, University of Pavia, Pavia, Italy (F.S.P.); Division of Micro- and Nanosystems, KTH Royal Institute of Technology, Stockholm, Sweden (Z.S.); and Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany (V.M.L.)
| | - Francesco S Paqualini
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (S.Y., A.M.K., L.P., Y.Z., J.X.S., S.K.G., R.Z.S., C.M.S., V.M.L.); Department of Drug Metabolism and Pharmacokinetics (DMPK), Merck KGaA, Darmstadt, Germany (L.P.); Department of Health Technology, Technical University of Denmark, Lyngby, Denmark (S.D.C., J.U.L.); Synthetic Physiology Laboratory, Department of Civil Engineering and Architecture, University of Pavia, Pavia, Italy (F.S.P.); Division of Micro- and Nanosystems, KTH Royal Institute of Technology, Stockholm, Sweden (Z.S.); and Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany (V.M.L.)
| | - Sravan K Goparaju
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (S.Y., A.M.K., L.P., Y.Z., J.X.S., S.K.G., R.Z.S., C.M.S., V.M.L.); Department of Drug Metabolism and Pharmacokinetics (DMPK), Merck KGaA, Darmstadt, Germany (L.P.); Department of Health Technology, Technical University of Denmark, Lyngby, Denmark (S.D.C., J.U.L.); Synthetic Physiology Laboratory, Department of Civil Engineering and Architecture, University of Pavia, Pavia, Italy (F.S.P.); Division of Micro- and Nanosystems, KTH Royal Institute of Technology, Stockholm, Sweden (Z.S.); and Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany (V.M.L.)
| | - Reza Zandi Shafagh
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (S.Y., A.M.K., L.P., Y.Z., J.X.S., S.K.G., R.Z.S., C.M.S., V.M.L.); Department of Drug Metabolism and Pharmacokinetics (DMPK), Merck KGaA, Darmstadt, Germany (L.P.); Department of Health Technology, Technical University of Denmark, Lyngby, Denmark (S.D.C., J.U.L.); Synthetic Physiology Laboratory, Department of Civil Engineering and Architecture, University of Pavia, Pavia, Italy (F.S.P.); Division of Micro- and Nanosystems, KTH Royal Institute of Technology, Stockholm, Sweden (Z.S.); and Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany (V.M.L.)
| | - Johan Ulrik Lind
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (S.Y., A.M.K., L.P., Y.Z., J.X.S., S.K.G., R.Z.S., C.M.S., V.M.L.); Department of Drug Metabolism and Pharmacokinetics (DMPK), Merck KGaA, Darmstadt, Germany (L.P.); Department of Health Technology, Technical University of Denmark, Lyngby, Denmark (S.D.C., J.U.L.); Synthetic Physiology Laboratory, Department of Civil Engineering and Architecture, University of Pavia, Pavia, Italy (F.S.P.); Division of Micro- and Nanosystems, KTH Royal Institute of Technology, Stockholm, Sweden (Z.S.); and Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany (V.M.L.)
| | - Carl M Sellgren
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (S.Y., A.M.K., L.P., Y.Z., J.X.S., S.K.G., R.Z.S., C.M.S., V.M.L.); Department of Drug Metabolism and Pharmacokinetics (DMPK), Merck KGaA, Darmstadt, Germany (L.P.); Department of Health Technology, Technical University of Denmark, Lyngby, Denmark (S.D.C., J.U.L.); Synthetic Physiology Laboratory, Department of Civil Engineering and Architecture, University of Pavia, Pavia, Italy (F.S.P.); Division of Micro- and Nanosystems, KTH Royal Institute of Technology, Stockholm, Sweden (Z.S.); and Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany (V.M.L.)
| | - Volker M Lauschke
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (S.Y., A.M.K., L.P., Y.Z., J.X.S., S.K.G., R.Z.S., C.M.S., V.M.L.); Department of Drug Metabolism and Pharmacokinetics (DMPK), Merck KGaA, Darmstadt, Germany (L.P.); Department of Health Technology, Technical University of Denmark, Lyngby, Denmark (S.D.C., J.U.L.); Synthetic Physiology Laboratory, Department of Civil Engineering and Architecture, University of Pavia, Pavia, Italy (F.S.P.); Division of Micro- and Nanosystems, KTH Royal Institute of Technology, Stockholm, Sweden (Z.S.); and Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany (V.M.L.)
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44
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Melliou S, Sangster KT, Djuric U, Diamandis P. The promise of organoids for unraveling the proteomic landscape of the developing human brain. Mol Psychiatry 2022; 27:73-80. [PMID: 34703024 DOI: 10.1038/s41380-021-01354-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 10/04/2021] [Accepted: 10/05/2021] [Indexed: 12/13/2022]
Abstract
Cerebral organoids offer an opportunity to bioengineer experimental avatars of the developing human brain and have already begun garnering relevant insights into complex neurobiological processes and disease. Thus far, investigations into their heterogeneous cellular composition and developmental trajectories have been largely limited to transcriptional readouts. Recent advances in global proteomic technologies have enabled a new range of techniques to explore dynamic and non-overlapping spatiotemporal protein-level programs operational in these humanoid neural structures. Here we discuss these early protein-based studies and their potentially essential role for unraveling critical secreted paracrine signals, processes with poor proteogenomic correlations, or neurodevelopmental proteins requiring post-translational modification for biological activity. Integrating emerging proteomic tools with these faithful human-derived neurodevelopmental models could transform our understanding of complex neural cell phenotypes and neurobiological processes, not exclusively driven by transcriptional regulation. These insights, less accessible by exclusive RNA-based approaches, could reveal new knowledge into human brain development and guide improvements in neural regenerative medicine efforts.
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Affiliation(s)
- Sofia Melliou
- Princess Margaret Cancer Centre, 101 College Street, Toronto, ON, M5G 1L7, Canada.,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5S 1A8, Canada
| | - Kevin T Sangster
- Princess Margaret Cancer Centre, 101 College Street, Toronto, ON, M5G 1L7, Canada
| | - Ugljesa Djuric
- Princess Margaret Cancer Centre, 101 College Street, Toronto, ON, M5G 1L7, Canada
| | - Phedias Diamandis
- Princess Margaret Cancer Centre, 101 College Street, Toronto, ON, M5G 1L7, Canada. .,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5S 1A8, Canada. .,Laboratory Medicine Program, University Health Network, 200 Elizabeth Street, Toronto, ON, M5G 2C4, Canada. .,Department of Medical Biophysics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
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45
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Josephine Boder E, Banerjee IA. Alzheimer's Disease: Current Perspectives and Advances in Physiological Modeling. Bioengineering (Basel) 2021; 8:211. [PMID: 34940364 PMCID: PMC8698996 DOI: 10.3390/bioengineering8120211] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 12/07/2021] [Accepted: 12/10/2021] [Indexed: 12/17/2022] Open
Abstract
Though Alzheimer's disease (AD) is the most common cause of dementia, complete disease-modifying treatments are yet to be fully attained. Until recently, transgenic mice constituted most in vitro model systems of AD used for preclinical drug screening; however, these models have so far failed to adequately replicate the disease's pathophysiology. However, the generation of humanized APOE4 mouse models has led to key discoveries. Recent advances in stem cell differentiation techniques and the development of induced pluripotent stem cells (iPSCs) have facilitated the development of novel in vitro devices. These "microphysiological" systems-in vitro human cell culture systems designed to replicate in vivo physiology-employ varying levels of biomimicry and engineering control. Spheroid-based organoids, 3D cell culture systems, and microfluidic devices or a combination of these have the potential to replicate AD pathophysiology and pathogenesis in vitro and thus serve as both tools for testing therapeutics and models for experimental manipulation.
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Affiliation(s)
| | - Ipsita A. Banerjee
- Department of Chemistry, Fordham University, 441 E. Fordham Road, Bronx, NY 10458, USA;
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46
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Valdoz JC, Johnson BC, Jacobs DJ, Franks NA, Dodson EL, Sanders C, Cribbs CG, Van Ry PM. The ECM: To Scaffold, or Not to Scaffold, That Is the Question. Int J Mol Sci 2021; 22:12690. [PMID: 34884495 PMCID: PMC8657545 DOI: 10.3390/ijms222312690] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 11/19/2021] [Accepted: 11/22/2021] [Indexed: 12/14/2022] Open
Abstract
The extracellular matrix (ECM) has pleiotropic effects, ranging from cell adhesion to cell survival. In tissue engineering, the use of ECM and ECM-like scaffolds has separated the field into two distinct areas-scaffold-based and scaffold-free. Scaffold-free techniques are used in creating reproducible cell aggregates which have massive potential for high-throughput, reproducible drug screening and disease modeling. Though, the lack of ECM prevents certain cells from surviving and proliferating. Thus, tissue engineers use scaffolds to mimic the native ECM and produce organotypic models which show more reliability in disease modeling. However, scaffold-based techniques come at a trade-off of reproducibility and throughput. To bridge the tissue engineering dichotomy, we posit that finding novel ways to incorporate the ECM in scaffold-free cultures can synergize these two disparate techniques.
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Affiliation(s)
| | | | | | | | | | | | | | - Pam M. Van Ry
- Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USA; (J.C.V.); (B.C.J.); (D.J.J.); (N.A.F.); (E.L.D.); (C.S.); (C.G.C.)
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47
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Kang Y, Zhou Y, Li Y, Han Y, Xu J, Niu W, Li Z, Liu S, Feng H, Huang W, Duan R, Xu T, Raj N, Zhang F, Dou J, Xu C, Wu H, Bassell GJ, Warren ST, Allen EG, Jin P, Wen Z. A human forebrain organoid model of fragile X syndrome exhibits altered neurogenesis and highlights new treatment strategies. Nat Neurosci 2021; 24:1377-1391. [PMID: 34413513 PMCID: PMC8484073 DOI: 10.1038/s41593-021-00913-6] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Accepted: 07/15/2021] [Indexed: 02/07/2023]
Abstract
Fragile X syndrome (FXS) is caused by the loss of fragile X mental retardation protein (FMRP), an RNA-binding protein that can regulate the translation of specific mRNAs. In this study, we developed an FXS human forebrain organoid model and observed that the loss of FMRP led to dysregulated neurogenesis, neuronal maturation and neuronal excitability. Bulk and single-cell gene expression analyses of FXS forebrain organoids revealed that the loss of FMRP altered gene expression in a cell-type-specific manner. The developmental deficits in FXS forebrain organoids could be rescued by inhibiting the phosphoinositide 3-kinase pathway but not the metabotropic glutamate pathway disrupted in the FXS mouse model. We identified a large number of human-specific mRNAs bound by FMRP. One of these human-specific FMRP targets, CHD2, contributed to the altered gene expression in FXS organoids. Collectively, our study revealed molecular, cellular and electrophysiological abnormalities associated with the loss of FMRP during human brain development.
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Affiliation(s)
- Yunhee Kang
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA;,Department of Biostatistics and Bioinformatics, Emory University School of Public Health, Atlanta, GA 30322, USA
| | - Ying Zhou
- Department of Psychiatry and Behavioral Scieces, Emory University School of Medicine, Atlanta, GA 30322, USA;,Department of Biostatistics and Bioinformatics, Emory University School of Public Health, Atlanta, GA 30322, USA
| | - Yujing Li
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA;,Department of Biostatistics and Bioinformatics, Emory University School of Public Health, Atlanta, GA 30322, USA
| | - Yanfei Han
- Department of Psychiatry and Behavioral Scieces, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Jie Xu
- The Graduate Program in Genetics and Molecular Biology, Emory University, GA 30322, USA
| | - Weibo Niu
- Department of Psychiatry and Behavioral Scieces, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Ziyi Li
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030
| | - Shiying Liu
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, OH 44106, USA
| | - Hao Feng
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, OH 44106, USA
| | - Wen Huang
- Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410078, China
| | - Ranhui Duan
- Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410078, China
| | - Tianmin Xu
- Department of Gynecology and Obstetrics, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Nisha Raj
- Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Feiran Zhang
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Juan Dou
- Department of Psychiatry and Behavioral Scieces, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Chongchong Xu
- Department of Psychiatry and Behavioral Scieces, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Hao Wu
- Department of Biostatistics and Bioinformatics, Emory University School of Public Health, Atlanta, GA 30322, USA
| | - Gary J Bassell
- Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Stephen T Warren
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Emily G Allen
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Peng Jin
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA;,To whom correspondence should be addressed: (P.J.) and (Z.W.)
| | - Zhexing Wen
- Department of Psychiatry and Behavioral Scieces, Emory University School of Medicine, Atlanta, GA 30322, USA;,Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA;,To whom correspondence should be addressed: (P.J.) and (Z.W.)
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48
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Vignon A, Salvador-Prince L, Lehmann S, Perrier V, Torrent J. Deconstructing Alzheimer's Disease: How to Bridge the Gap between Experimental Models and the Human Pathology? Int J Mol Sci 2021; 22:8769. [PMID: 34445475 PMCID: PMC8395727 DOI: 10.3390/ijms22168769] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 08/05/2021] [Accepted: 08/06/2021] [Indexed: 02/07/2023] Open
Abstract
Discovered more than a century ago, Alzheimer's disease (AD) is not only still present in our societies but has also become the most common dementia, with 50 million people worldwide affected by the disease. This number is expected to double in the next generation, and no cure is currently available to slow down or stop the disease progression. Recently, some advances were made due to the approval of the aducanumab treatment by the American Food and Drug Administration. The etiology of this human-specific disease remains poorly understood, and the mechanisms of its development have not been completely clarified. Several hypotheses concerning the molecular mechanisms of AD have been proposed, but the existing studies focus primarily on the two main markers of the disease: the amyloid β peptides, whose aggregation in the brain generates amyloid plaques, and the abnormally phosphorylated tau proteins, which are responsible for neurofibrillary tangles. These protein aggregates induce neuroinflammation and neurodegeneration, which, in turn, lead to cognitive and behavioral deficits. The challenge is, therefore, to create models that best reproduce this pathology. This review aims at gathering the different existing AD models developed in vitro, in cellulo, and in vivo. Many models have already been set up, but it is necessary to identify the most relevant ones for our investigations. The purpose of the review is to help researchers to identify the most pertinent disease models, from the most often used to the most recently generated and from simple to complex, explaining their specificities and giving concrete examples.
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Affiliation(s)
- Anaïs Vignon
- INM, University of Montpellier, INSERM, 34095 Montpellier, France; (A.V.); (L.S.-P.)
| | - Lucie Salvador-Prince
- INM, University of Montpellier, INSERM, 34095 Montpellier, France; (A.V.); (L.S.-P.)
| | - Sylvain Lehmann
- INM, University of Montpellier, INSERM, CHU Montpellier, 34095 Montpellier, France;
| | - Véronique Perrier
- INM, University of Montpellier, INSERM, CNRS, 34095 Montpellier, France
| | - Joan Torrent
- INM, University of Montpellier, INSERM, 34095 Montpellier, France; (A.V.); (L.S.-P.)
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49
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Ryu WI, Cohen BM, Sonntag KC. Hypothesis and Theory: Characterizing Abnormalities of Energy Metabolism Using a Cellular Platform as a Personalized Medicine Approach for Alzheimer's Disease. Front Cell Dev Biol 2021; 9:697578. [PMID: 34395428 PMCID: PMC8363296 DOI: 10.3389/fcell.2021.697578] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 06/27/2021] [Indexed: 01/07/2023] Open
Abstract
Sporadic or late-onset Alzheimer's disease (LOAD) is characterized by slowly progressive deterioration and death of CNS neurons. There are currently no substantially disease-modifying therapies. LOAD pathology is closely related to changes with age and include, among others, accumulation of toxic molecules and altered metabolic, microvascular, biochemical and inflammatory processes. In addition, there is growing evidence that cellular energy deficits play a critical role in aging and LOAD pathophysiology. However, the exact mechanisms and causal relationships are largely unknown. In our studies we tested the hypothesis that altered bioenergetic and metabolic cell functions are key elements in LOAD, using a cellular platform consisting of skin fibroblasts derived from LOAD patients and AD-unaffected control individuals and therefrom generated induced pluripotent stem cells that are differentiated to brain-like cells to study LOAD pathogenic processes in context of age, disease, genetic background, cell development, and cell type. This model has revealed that LOAD cells exhibit a multitude of bioenergetic and metabolic alterations, providing evidence for an innate inefficient cellular energy management in LOAD as a prerequisite for the development of neurodegenerative disease with age. We propose that this cellular platform could ultimately be used as a conceptual basis for a personalized medicine tool to predict altered aging and risk for development of dementia, and to test or implement customized therapeutic or disease-preventive intervention strategies.
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Affiliation(s)
- Woo-In Ryu
- Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, United States
- Basic Neuroscience Division, McLean Hospital, Harvard Medical School, Belmont, MA, United States
- Program for Neuropsychiatric Research, McLean Hospital, Harvard Medical School, Belmont, MA, United States
| | - Bruce M. Cohen
- Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, United States
- Program for Neuropsychiatric Research, McLean Hospital, Harvard Medical School, Belmont, MA, United States
- Psychotic Disorders Division, McLean Hospital, Harvard Medical School, Belmont, MA, United States
| | - Kai-C. Sonntag
- Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, United States
- Basic Neuroscience Division, McLean Hospital, Harvard Medical School, Belmont, MA, United States
- Program for Neuropsychiatric Research, McLean Hospital, Harvard Medical School, Belmont, MA, United States
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50
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Trudler D, Ghatak S, Lipton SA. Emerging hiPSC Models for Drug Discovery in Neurodegenerative Diseases. Int J Mol Sci 2021; 22:8196. [PMID: 34360966 PMCID: PMC8347370 DOI: 10.3390/ijms22158196] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/26/2021] [Accepted: 07/27/2021] [Indexed: 12/12/2022] Open
Abstract
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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Affiliation(s)
- Dorit Trudler
- Neurodegeneration New Medicines Center and Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA; (D.T.); (S.G.)
| | - Swagata Ghatak
- Neurodegeneration New Medicines Center and Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA; (D.T.); (S.G.)
| | - Stuart A. Lipton
- Neurodegeneration New Medicines Center and Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA; (D.T.); (S.G.)
- Department of Neurosciences, University of California San Diego School of Medicine, La Jolla, CA 92093, USA
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