Soluble Gamma-secretase Modulators Attenuate Alzheimer's β-amyloid Pathology and Induce Conformational Changes in Presenilin 1

被引：25

作者：

Raven, Frank ^{[1
,2
]}

Ward, Joseph F. ^{[1
]}

Zoltowska, Katarzyna M. ^{[3
]}

Wan, Yu ^{[1
,4
]}

Bylykbashi, Enjana ^{[1
]}

Miller, Sean J. ^{[1
]}

Shen, Xunuo ^{[1
]}

Choi, Se Hoon ^{[1
]}

Rynearson, Kevin D. ^{[5
]}

Berezovska, Oksana ^{[3
]}

Wagner, Steven L. ^{[5
,6
]}

Tanzi, Rudolph E. ^{[1
]}

Zhang, Can ^{[1
]}

机构：

[1] Harvard Med Sch, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis MIND, Genet & Aging Res Unit,Dept Neurol, Charlestown, MA 02129 USA

[2] Univ Groningen, Groningen Inst Evolutionary Life Sci, NL-9747 AG Groningen, Netherlands

[3] Harvard Med Sch, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis MIND, Alzheimer Res Unit,Dept Neurol, Charlestown, MA 02129 USA

[4] Qingdao Univ, Qingdao Municipal Hosp, Dept Neurol, Qingdao, Peoples R China

[5] Univ Calif La Jolla, Dept Neurosci, San Diego, CA 92093 USA

[6] VA San Diego Healthcare Syst, La Jolla, CA 92161 USA

来源：

EBIOMEDICINE | 2017年 / 24卷

关键词：

Alzheimer's disease; beta-amyloid; beta-amyloid precursor protein; gamma-secretase; gamma-secretase modulator; Notch; TRANSGENIC MOUSE MODEL; PRECURSOR PROTEIN; SYNAPTOTAGMIN; IN-VIVO; A-BETA; DISEASE; APP; DEPOSITION; INHIBITOR; MEMBRANE;

D O I：

10.1016/j.ebiom.2017.08.028

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

A central pathogenic event of Alzheimer's disease (AD) is the accumulation of the A beta 42 peptide, which is generated from amyloid-beta precursor protein (APP) via cleavages by beta- and gamma-secretase. We have developed a class of soluble 2-aminothiazole gamma-secretase modulators (SGSMs) that preferentially decreases A beta 42 levels. However, the effects of SGSMs in AD animals and cells expressing familial AD mutations, as well as the mechanism of gamma-secretase modulation remain largely unknown. Here, a representative of this SGSM scaffold, SGSM-36, was investigated using animals and cells expressing FAD mutations. SGSM-36 preferentially reduced A beta 42 levels without affecting either alpha- and beta-secretase processing of APP nor Notch processing. Furthermore, an allosteric site was identified within the gamma-secretase complex that allowed access of SGSM-36 using cell-based, fluorescence lifetime imaging microscopy analysis. Collectively, these studies provide mechanistic insights regarding SGSMs of this class and reinforce their therapeutic potential in AD. (C) 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license

引用

页码：93 / 101

页数：9

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