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In vitro Models of Neurodegenerative Diseases.

ABSTRACT: Neurodegenerative diseases are progressive degenerative conditions characterized by the functional deterioration and ultimate loss of neurons. These incurable and debilitating diseases affect millions of people worldwide, and therefore represent a major global health challenge with severe implications for individuals and society. Recently, several neuroprotective drugs have failed in human clinical trials despite promising pre-clinical data, suggesting that conventional cell cultures and animal models cannot precisely replicate human pathophysiology. To bridge the gap between animal and human studies, three-dimensional cell culture models have been developed from human or animal cells, allowing the effects of new therapies to be predicted more accurately by closely replicating some aspects of the brain environment, mimicking neuronal and glial cell interactions, and incorporating the effects of blood flow. In this review, we discuss the relative merits of different cerebral models, from traditional cell cultures to the latest high-throughput three-dimensional systems. We discuss their advantages and disadvantages as well as their potential to investigate the complex mechanisms of human neurodegenerative diseases. We focus on in vitro models of the most frequent age-related neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease and prion disease, and on multiple sclerosis, a chronic inflammatory neurodegenerative disease affecting young adults.

SUBMITTER: Slanzi A

PROVIDER: S-EPMC7247860 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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<i>In vitro</i> Models of Neurodegenerative Diseases.

Slanzi Anna A Iannoto Giulia G Rossi Barbara B Zenaro Elena E Constantin Gabriela G

Frontiers in cell and developmental biology 20200513

Neurodegenerative diseases are progressive degenerative conditions characterized by the functional deterioration and ultimate loss of neurons. These incurable and debilitating diseases affect millions of people worldwide, and therefore represent a major global health challenge with severe implications for individuals and society. Recently, several neuroprotective drugs have failed in human clinical trials despite promising pre-clinical data, suggesting that conventional cell cultures and animal ...[more]

PMID: 32528949

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Project description:Neurodegenerative diseases of the central nervous system are characterised by pathogenetic cellular and molecular changes in specific areas of the brain that lead to the dysfunction and/or loss of explicit neuronal populations. Despite exhibiting different clinical profiles and selective neuronal loss, common features such as abnormal protein deposition, dysfunctional cellular transport, mitochondrial deficits, glutamate excitotoxicity and inflammation are observed in most, if not all, neurodegenerative disorders, suggesting converging pathways of neurodegeneration. We have generated comparative genome-wide gene expression data for Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, multiple sclerosis, Parkinson’s disease and schizophrenia using an extensive cohort of well characterised post-mortem CNS tissues. The analysis of whole genome expression patterns across these major disorders offers an outstanding opportunity not only to look into exclusive disease specific changes, but more importantly to uncover potential common molecular pathogenic mechanisms that could be targeted for therapeutic gain. Surprisingly, no dysregulated gene that passed our selection criteria was found in common across all 6 diseases using our primary method of analysis. However, 61 dysregulated genes were shared when comparing five and four diseases. Our analysis indicates firstly the involvement of common neuronal homeostatic, survival and synaptic plasticity pathways. Secondly, we report changes to immunoregulatory and immunomodulatory pathways in all diseases. Our secondary method of analysis confirmed significant up-regulation of a number of genes in diseases presenting degeneration and showed that somatostatin was downregulated in all 6 diseases. The latter is supportive of a general role for neuroinflammation in the pathogenesis and/or response to neurodegeneration. Unravelling the detailed nature of the molecular changes regulating inflammation in the CNS is key to the development of novel therapeutic approaches for these chronic conditions. A total of 113 cases were selected retrospectively on the basis of a confirmed clinical and neuropathological diagnosis and snap-frozen brain blocks were provided by various tissue banks within the BrainNet Europe network. Total RNA was extracted from dissected snap-frozen tissue (< 100 mg) by the individual laboratories according to a BNE optimised common protocol using the RNeasy(r) tissue lipid mini kit (Qiagen Ltd, Crawley, UK) according to the manufacturer's instructions, and was stored at -80C until further use. Gene expression analysis was performed on the RNA samples using the Illumina whole genome HumanRef8 v2 BeadChip (Illumina, London, UK). All the labelling and hybridisation of the samples was carried out in a single experiment by the Imperial College group to reduce the technical variability. RNA samples were prepared for array analysis using the Illumina TotalPrep(tm)-96 RNA Amplification Kit (Ambion/Applied Biosystems, Warrington, UK). Finally, the BeadChips we re scanned using the Illumina BeadArray Reader. The data was extracted using BeadStudio 3.2 (Illumina). Data normalisation and gene differential expression analyses were conducted using the Rosetta error models available in the Rosetta Resolver(r) system (Rosetta Biosoftware, Seattle, Wa, USA). Two samples presented very low signal expression most likely due to hybridization problems and did not pass the quality control test. They are not represented here. One of the 2 samples was a replicate, therefore there was loss of only 1 case bringing the grand total of cases used to 112 (total of samples of 118 including 6 replicates).

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In vitro Models of Neurodegenerative Diseases.

Publications

<i>In vitro</i> Models of Neurodegenerative Diseases.

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