title: GATA1-mediated transcriptional regulation of the γ-secretase activating protein increases Aβ formation in Down syndrome.
abstract: Because of an extra copy of the Aβ precursor protein gene on chromosome 21, Down syndrome (DS) individuals develop high levels of Aβ peptides and Alzheimer disease-like brain amyloidosis early in life. Here we show that the γ-secretase activating protein (GSAP), a key enzyme in amyloidogenesis, is increased in DS brains and specifically regulated at the transcriptional level by GATA1 transcription factor. The discovery of this novel pathway has translational implications for DS, because pharmacological inhibition of GSAP is an attractive and viable Aβ-lowering therapeutic strategy for this disorder.
authors.affiliation: Department of Pharmacology and Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA.
authors.forename: Jin
authors.initials: J
authors.lastname: Chu
authors.affiliation: Departments of Neurology, Psychiatry, and Pathology, and Center for Cognitive Neurology, New York University School of Medicine, New York, NY.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wisniewski
authors.affiliation: Department of Pharmacology and Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA.
authors.forename: Domenico
authors.initials: D
authors.lastname: Praticò
mesh_terms: D000368:Aged; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D004314:Down Syndrome / Q000378:metabolism*; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism*; D050982:GATA1 Transcription Factor / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011506:Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D016229:Amyloid beta-Peptides; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; C552289:GSAP protein, human; D011506:Proteins; D012333:RNA, Messenger