title: Bioactive Compound Screen for Pharmacological Enhancers of Apolipoprotein E in Primary Human Astrocytes.
abstract: Pharmacological screening in physiologically relevant brain cells is crucial for identifying neuroactive compounds that better translate into in vivo biology and efficacious therapeutics. Pharmacological enhancement of apolipoprotein E (apoE), a cholesterol-transporting apolipoprotein, has been proposed as a promising therapeutic approach for Alzheimer's disease. Several nuclear receptor agonists were initially shown to increase brain apoE levels together with ATP-binding cassette transporter 1 (ABCA1), but their underlying mechanisms remain unclear. To gain an insight on brain apoE regulation, we performed an unbiased high-throughput screening of known drugs and bioactive compounds in cultured human primary astrocytes, the major apoE-producing cell type in the brain. We have identified several small molecules that increase apoE secretion via previously unknown mechanisms, including those not co-inducing ABCA1. These newly identified compounds are active preferentially in human astrocytes but not in an astrocytoma cell line, furnishing new tools for investigating biological pathways underlying brain apoE production.
authors.affiliation: Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, 630 West 168th Street, P&S12-430, New York, NY 10032, USA.
authors.forename: Gina M
authors.initials: GM
authors.lastname: Finan
authors.affiliation: High Throughput Screening Center, Judith P. Sulzberger Genome Center, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Realubit
authors.affiliation: Department of Physiology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 440-746, South Korea.
authors.forename: Sungkwon
authors.initials: S
authors.lastname: Chung
authors.affiliation: Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Lütjohann
authors.affiliation: The Division of Molecular Medicine, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Cirrito
authors.affiliation: High Throughput Screening Center, Judith P. Sulzberger Genome Center, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Karan
authors.affiliation: Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, 630 West 168th Street, P&S12-430, New York, NY 10032, USA. Electronic address: twk16@cumc.columbia.edu.
authors.forename: Tae-Wan
authors.initials: TW
authors.lastname: Kim
keywords: Alzheimer's disease; apolipoprotein E (apoE); astrocyte; chemical biology; cholesterol; drug discovery; high-throughput screening (HTS); phenotypic screening; primary cells