Characterization and Molecular Profiling of PSEN1 Familial Alzheimer's Disease iPSC-Derived Neural Progenitors

被引：134

作者：

Sproul, Andrew A. ^{[1
]}

Jacob, Samson ^{[1
]}

Pre, Deborah ^{[2
,3
]}

Kim, Soong Ho ^{[4
,5
,6
]}

Nestor, Michael W. ^{[1
]}

Navarro-Sobrino, Miriam ^{[7
]}

Santa-Maria, Ismael ^{[2
,3
]}

Zimmer, Matthew ^{[1
]}

Aubry, Soline ^{[2
,3
]}

Steele, John W. ^{[4
,5
,6
]}

Kahler, David J. ^{[1
]}

Dranovsky, Alex ^{[7
]}

Arancio, Ottavio ^{[2
,3
]}

Crary, John F. ^{[2
,3
]}

Gandy, Sam ^{[4
,5
,6
,8
]}

Noggle, Scott A. ^{[1
]}

机构：

[1] New York Stem Cell Fdn, New York, NY 10023 USA

[2] Columbia Univ, Dept Pathol & Cell Biol, New York, NY USA

[3] Columbia Univ, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA

[4] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY USA

[5] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY USA

[6] Icahn Sch Med Mt Sinai, Alzheimers Dis Res Ctr, New York, NY USA

[7] Columbia Univ, Dept Psychiat, New York, NY USA

[8] James J Peters Vet Adm Med Ctr, Bronx, NY USA

来源：

PLOS ONE | 2014年 / 9卷 / 01期

基金：

美国国家卫生研究院;

关键词：

PLURIPOTENT STEM-CELLS; 21ST-CENTURY BRAIN BANKING; NEURONAL GENE-EXPRESSION; COLUMBIA-UNIVERSITY; ADULT NEUROGENESIS; TRANSGENIC MICE; HUMAN ES; A-BETA; PRESENILIN-1; ACTIVATION;

D O I：

10.1371/journal.pone.0084547

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Presenilin 1 (PSEN1) encodes the catalytic subunit of gamma-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 A beta 42 to A beta 40 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 A beta 42/40, and have characterized novel expression changes.

引用

页数：11

共 52 条

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