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PLoS One. 2014 Jan 8;9(1):e84547. doi: 10.1371/journal.pone.0084547. eCollection 2014.

Characterization and molecular profiling of PSEN1 familial Alzheimer's disease iPSC-derived neural progenitors.

Author information

1
The New York Stem Cell Foundation, New York, New York, United States of America.
2
Department of Pathology & Cell Biology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America.
3
Departments of Neurology and Psychiatry and the Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
4
Department of Psychiatry, Columbia University, New York, New York, United States of America.
5
Departments of Neurology and Psychiatry and the Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America ; James J Peters Veterans Administration Medical Center, Bronx, New York, United States of America.

Abstract

Presenilin 1 (PSEN1) encodes the catalytic subunit of γ-secretase, and PSEN1 mutations are the most common cause of early onset familial Alzheimer's disease (FAD). In order to elucidate pathways downstream of PSEN1, we characterized neural progenitor cells (NPCs) derived from FAD mutant PSEN1 subjects. Thus, we generated induced pluripotent stem cells (iPSCs) from affected and unaffected individuals from two families carrying PSEN1 mutations. PSEN1 mutant fibroblasts, and NPCs produced greater ratios of Aβ42 to Aβ40 relative to their control counterparts, with the elevated ratio even more apparent in PSEN1 NPCs than in fibroblasts. Molecular profiling identified 14 genes differentially-regulated in PSEN1 NPCs relative to control NPCs. Five of these targets showed differential expression in late onset AD/Intermediate AD pathology brains. Therefore, in our PSEN1 iPSC model, we have reconstituted an essential feature in the molecular pathogenesis of FAD, increased generation of Aβ42/40, and have characterized novel expression changes.

PMID:
24416243
PMCID:
PMC3885572
DOI:
10.1371/journal.pone.0084547
[Indexed for MEDLINE]
Free PMC Article

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