Pharmacological Assessment of <i>γ</i>-Secretase Activity from Rodent and Human Brain

• 作者: Bruce A. Maguire Christine E. Oborski Christine Parker Douglas S. Johnson Gary Bora Kathleen Wood Kelly R. Bales Kevin Atchison Martin Pettersson Nikolay Pozdnyakov Rathna Iyer Timothy A. Subashi
• 来源期刊: 神经系统科学与医药(英文)
• 学科: 医学
• 关键词: Alzheimer’s Disease Amyloid Precursor Protein Aβ Γ-SECRETASE Pharmacology
• 年，卷（期）: 2012,（2）
• 页码范围: 149-161
• 页数: 13页
• 分类号: R73

摘要

γ-Secretase is involved in the final processing of the amyloid precursor protein into a heterogeneous pool of β-amyloid (Aβ) peptides. Current Alzheimer’s disease drug discovery efforts include targeting γ-secretase activity in brain to attenuate production of the neurotoxic Aβ species. The resulting pharmacology may be affected by species-specific differences in the γ-secretase core complex or its associated proteins. Therefore, we utilized partially purified γ-secretase membranes derived from the brains of different species, including human cortex, to quantitatively assess the de novo production of both Aβ42 and Aβ40 following treatment with known γ-secretase inhibitors and modulators. We determined that the inhibitory activity of a Notch-1 sparing γ-secretase inhibitor and the modulatory activity of two classes of γ-secretase modulators were equipotent at affecting the production of Aβ across rodent and human brain membrane preparations. Additionally, the observed modulator-specific Aβ profile in isolated brain membranes across species was similar to that observed in HeLa cell membranes, and the brain and CSF of guinea pigs following oral administration. By utilizing rapidly purified γ-secretase, we were able to probe and compare the complex pharmacology of γ-secretase in the brain across common rodent species and human cortex.