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A human stem cell model of early Alzheimer's disease pathology in Down syndrome.
- Source :
-
Science translational medicine [Sci Transl Med] 2012 Mar 07; Vol. 4 (124), pp. 124ra29. Date of Electronic Publication: 2012 Feb 15. - Publication Year :
- 2012
-
Abstract
- Human cellular models of Alzheimer's disease (AD) pathogenesis would enable the investigation of candidate pathogenic mechanisms in AD and the testing and developing of new therapeutic strategies. We report the development of AD pathologies in cortical neurons generated from human induced pluripotent stem (iPS) cells derived from patients with Down syndrome. Adults with Down syndrome (caused by trisomy of chromosome 21) develop early-onset AD, probably due to increased expression of a gene on chromosome 21 that encodes the amyloid precursor protein (APP). We found that cortical neurons generated from iPS cells and embryonic stem cells from Down syndrome patients developed AD pathologies over months in culture, rather than years in vivo. These cortical neurons processed the transmembrane APP protein, resulting in secretion of the pathogenic peptide fragment amyloid-β42 (Aβ42), which formed insoluble intracellular and extracellular amyloid aggregates. Production of Aβ peptides was blocked by a γ-secretase inhibitor. Finally, hyperphosphorylated tau protein, a pathological hallmark of AD, was found to be localized to cell bodies and dendrites in iPS cell-derived cortical neurons from Down syndrome patients, recapitulating later stages of the AD pathogenic process.
- Subjects :
- Alzheimer Disease metabolism
Amyloid beta-Peptides metabolism
Amyloid beta-Protein Precursor metabolism
Cell Differentiation
Cell Line
Down Syndrome metabolism
Electrophysiology
Embryonic Stem Cells cytology
Humans
Immunohistochemistry
Induced Pluripotent Stem Cells cytology
tau Proteins metabolism
Alzheimer Disease pathology
Down Syndrome pathology
Embryonic Stem Cells metabolism
Induced Pluripotent Stem Cells metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1946-6242
- Volume :
- 4
- Issue :
- 124
- Database :
- MEDLINE
- Journal :
- Science translational medicine
- Publication Type :
- Academic Journal
- Accession number :
- 22344463
- Full Text :
- https://doi.org/10.1126/scitranslmed.3003771