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Self-Organizing 3D Human Neural Tissue Derived from Induced Pluripotent Stem Cells Recapitulate Alzheimer's Disease Phenotypes
- Source :
- PLoS ONE, Vol 11, Iss 9, p e0161969 (2016), PLOS, PLoS ONE
- Publication Year :
- 2016
- Publisher :
- Public Library of Science (PLoS), 2016.
-
Abstract
- The dismal success rate of clinical trials for Alzheimer's disease (AD) motivates us to develop model systems of AD pathology that have higher predictive validity. The advent of induced pluripotent stem cells (iPSCs) allows us to model pathology and study disease mechanisms directly in human neural cells from healthy individual as well as AD patients. However, two-dimensional culture systems do not recapitulate the complexity of neural tissue, and phenotypes such as extracellular protein aggregation are difficult to observe. We report brain organoids that use pluripotent stem cells derived from AD patients and recapitulate AD-like pathologies such as amyloid aggregation, hyperphosphorylated tau protein, and endosome abnormalities. These pathologies are observed in an age-dependent manner in organoids derived from multiple familial AD (fAD) patients harboring amyloid precursor protein (APP) duplication or presenilin1 (PSEN1) mutation, compared to controls. The incidence of AD pathology was consistent amongst several fAD lines, which carried different mutations. Although these are complex assemblies of neural tissue, they are also highly amenable to experimental manipulation. We find that treatment of patient-derived organoids with β- and γ-secretase inhibitors significantly reduces amyloid and tau pathology. Moreover, these results show the potential of this model system to greatly increase the translatability of pre-clinical drug discovery in AD.
- Subjects :
- 0301 basic medicine
lcsh:Medicine
Protein aggregation
medicine.disease_cause
Animal Cells
Medicine and Health Sciences
Amyloid precursor protein
PSEN1
Organ Cultures
Enzyme-Linked Immunoassays
Phosphorylation
Induced pluripotent stem cell
lcsh:Science
Neurons
Mutation
Multidisciplinary
Tissue Scaffolds
biology
Stem Cells
Physics
Brain
Neurodegenerative Diseases
Condensed Matter Physics
Phenotype
3. Good health
Organoids
Neurology
Physical Sciences
Biological Cultures
Cellular Structures and Organelles
Cellular Types
Research Article
Amyloid
Induced Pluripotent Stem Cells
Tau protein
tau Proteins
Endosomes
Research and Analysis Methods
Cell Line
03 medical and health sciences
Alzheimer Disease
Mental Health and Psychiatry
medicine
Humans
Vesicles
Particle Size
Immunoassays
Immunohistochemistry Techniques
Amyloid beta-Peptides
lcsh:R
Biology and Life Sciences
Cell Biology
Histochemistry and Cytochemistry Techniques
030104 developmental biology
Cellular Neuroscience
Immunology
Immunologic Techniques
biology.protein
Dementia
lcsh:Q
Neuroscience
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 11
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....ff8a04cd28d48c147ac1cdae3555d020