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      Modeling neurodegenerative diseases with cerebral organoids and other three-dimensional culture systems: focus on Alzheimer’s disease

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          Abstract

          Many neurodegenerative diseases (NDs) such as Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, amyotrophic lateral sclerosis and Huntington’s disease, are characterized by the progressive accumulation of abnormal proteinaceous assemblies in specific cell types and regions of the brain, leading to cellular dysfunction and brain damage. Although animal- and in vitro-based studies of NDs have provided the field with an extensive understanding of some of the mechanisms underlying these diseases, findings from these studies have not yielded substantial progress in identifying treatment options for patient populations. This necessitates the development of complementary model systems that are better suited to recapitulate human-specific features of ND pathogenesis. Three-dimensional (3D) culture systems, such as cerebral organoids generated from human induced pluripotent stem cells, hold significant potential to model NDs in a complex, tissue-like environment. In this review, we discuss the advantages of 3D culture systems and 3D modeling of NDs, especially AD and FTD. We also provide an overview of the challenges and limitations of the current 3D culture systems. Finally, we propose a few potential future directions in applying state-of-the-art technologies in 3D culture systems to understand the mechanisms of NDs and to accelerate drug discovery.

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          Cerebral organoids model human brain development and microcephaly

          The complexity of the human brain has made it difficult to study many brain disorders in model organisms, and highlights the need for an in vitro model of human brain development. We have developed a human pluripotent stem cell-derived 3D organoid culture system, termed cerebral organoid, which develops various discrete though interdependent brain regions. These include cerebral cortex containing progenitor populations that organize and produce mature cortical neuron subtypes. Furthermore, cerebral organoids recapitulate features of human cortical development, namely characteristic progenitor zone organization with abundant outer radial glial stem cells. Finally, we use RNAi and patient-specific iPS cells to model microcephaly, a disorder that has been difficult to recapitulate in mice. We demonstrate premature neuronal differentiation in patient organoids, a defect that could explain the disease phenotype. Our data demonstrate that 3D organoids can recapitulate development and disease of even this most complex human tissue.
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            Neurological associations of COVID-19

            Summary Background The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is of a scale not seen since the 1918 influenza pandemic. Although the predominant clinical presentation is with respiratory disease, neurological manifestations are being recognised increasingly. On the basis of knowledge of other coronaviruses, especially those that caused the severe acute respiratory syndrome and Middle East respiratory syndrome epidemics, cases of CNS and peripheral nervous system disease caused by SARS-CoV-2 might be expected to be rare. Recent developments A growing number of case reports and series describe a wide array of neurological manifestations in 901 patients, but many have insufficient detail, reflecting the challenge of studying such patients. Encephalopathy has been reported for 93 patients in total, including 16 (7%) of 214 hospitalised patients with COVID-19 in Wuhan, China, and 40 (69%) of 58 patients in intensive care with COVID-19 in France. Encephalitis has been described in eight patients to date, and Guillain-Barré syndrome in 19 patients. SARS-CoV-2 has been detected in the CSF of some patients. Anosmia and ageusia are common, and can occur in the absence of other clinical features. Unexpectedly, acute cerebrovascular disease is also emerging as an important complication, with cohort studies reporting stroke in 2–6% of patients hospitalised with COVID-19. So far, 96 patients with stroke have been described, who frequently had vascular events in the context of a pro-inflammatory hypercoagulable state with elevated C-reactive protein, D-dimer, and ferritin. Where next? Careful clinical, diagnostic, and epidemiological studies are needed to help define the manifestations and burden of neurological disease caused by SARS-CoV-2. Precise case definitions must be used to distinguish non-specific complications of severe disease (eg, hypoxic encephalopathy and critical care neuropathy) from those caused directly or indirectly by the virus, including infectious, para-infectious, and post-infectious encephalitis, hypercoagulable states leading to stroke, and acute neuropathies such as Guillain-Barré syndrome. Recognition of neurological disease associated with SARS-CoV-2 in patients whose respiratory infection is mild or asymptomatic might prove challenging, especially if the primary COVID-19 illness occurred weeks earlier. The proportion of infections leading to neurological disease will probably remain small. However, these patients might be left with severe neurological sequelae. With so many people infected, the overall number of neurological patients, and their associated health burden and social and economic costs might be large. Health-care planners and policy makers must prepare for this eventuality, while the many ongoing studies investigating neurological associations increase our knowledge base.
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              Single-cell transcriptomic analysis of Alzheimer’s disease

              Alzheimer's disease is a pervasive neurodegenerative disorder, the molecular complexity of which remains poorly understood. Here, we analysed 80,660 single-nucleus transcriptomes from the prefrontal cortex of 48 individuals with varying degrees of Alzheimer's disease pathology. Across six major brain cell types, we identified transcriptionally distinct subpopulations, including those associated with pathology and characterized by regulators of myelination, inflammation, and neuron survival. The strongest disease-associated changes appeared early in pathological progression and were highly cell-type specific, whereas genes upregulated at late stages were common across cell types and primarily involved in the global stress response. Notably, we found that female cells were overrepresented in disease-associated subpopulations, and that transcriptional responses were substantially different between sexes in several cell types, including oligodendrocytes. Overall, myelination-related processes were recurrently perturbed in multiple cell types, suggesting that myelination has a key role in Alzheimer's disease pathophysiology. Our single-cell transcriptomic resource provides a blueprint for interrogating the molecular and cellular basis of Alzheimer's disease.
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                Author and article information

                Contributors
                Mark.Hester@nationwidechildrens.org
                Hongjun.Fu@osumc.edu
                Journal
                Stem Cell Rev Rep
                Stem Cell Rev Rep
                Stem Cell Reviews and Reports
                Springer US (New York )
                2629-3269
                2629-3277
                12 November 2020
                : 1-22
                Affiliations
                [1 ]GRID grid.412332.5, ISNI 0000 0001 1545 0811, Department of Neuroscience, , The Ohio State University Wexner Medical Center, ; 616 Biomedical Research Tower, 460 W. 12th Ave, Columbus, OH 43210 USA
                [2 ]GRID grid.240344.5, ISNI 0000 0004 0392 3476, The Steve and Cindy Rasmussen Institute for Genomic Medicine, , Abigail Wexner Research Institute at Nationwide Children’s Hospital, ; 575 Children’s Crossroad, Columbus, OH 43215 USA
                [3 ]GRID grid.412332.5, ISNI 0000 0001 1545 0811, College of Medicine, , The Ohio State University Wexner Medical Center, ; Columbus, OH USA
                [4 ]GRID grid.261331.4, ISNI 0000 0001 2285 7943, College of Pharmacy, , The Ohio State University, ; Columbus, OH USA
                [5 ]GRID grid.412332.5, ISNI 0000 0001 1545 0811, Department of Pediatrics, , The Ohio State University Wexner Medical Center, ; Columbus, OH USA
                Author notes

                This article belongs to the Topical Collection: Special issue on Neurogenesis and Neurodegeneration: Basic Research and Clinic Applications

                Guest Editor: Henning Ulrich

                Author information
                http://orcid.org/0000-0001-5346-7075
                Article
                10068
                10.1007/s12015-020-10068-9
                7658915
                33180261
                e54331f8-2492-491f-b467-60b45bd90fd6
                © Springer Science+Business Media, LLC, part of Springer Nature 2020

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 25 October 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000009, Foundation for the National Institutes of Health;
                Award ID: AG056673
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000957, Alzheimer's Association;
                Award ID: AARF-17-505009
                Award Recipient :
                Funded by: Neuroscience Research Institute and Chronic Brain Injury Pilot Award
                Funded by: FundRef http://dx.doi.org/10.13039/100011500, Research Institute, Nationwide Children's Hospital;
                Funded by: FundRef http://dx.doi.org/10.13039/100000005, U.S. Department of Defense;
                Award ID: W81XWH1910309
                Award Recipient :
                Categories
                Article

                alzheimer’s disease,neurodegenerative diseases,hipscs,3d culture,cerebral organoids,tau pathology

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