Modulation of γ-Secretase Reduces β-Amyloid Deposition in a Transgenic Mouse Model of Alzheimer's Disease

被引：207

作者：

Kounnas, Maria Z. ^{[4
]}

Danks, Anne M. ^{[4
]}

Cheng, Soan ^{[4
]}

Tyree, Curtis ^{[4
]}

Ackerman, Elizabeth ^{[4
]}

Zhang, Xulun ^{[1
]}

Ahn, Kwangwook ^{[2
]}

Nguyen, Phuong ^{[4
]}

Comer, Dan ^{[4
]}

Mao, Long ^{[4
]}

Yu, Chengzhi ^{[4
]}

Pleynet, David ^{[4
]}

Digregorio, Paul J. ^{[4
]}

Velicelebi, Gonul ^{[4
]}

Stauderman, Kenneth A. ^{[4
]}

Comer, William T. ^{[4
]}

Mobley, William C. ^{[5
]}

Li, Yue-Ming ^{[2
]}

Sisodia, Sangram S. ^{[1
]}

Tanzi, Rudolph E. ^{[3
]}

Wagner, Steven L. ^{[4
]}

机构：

[1] Univ Chicago, Ctr Mol Neurobiol, Chicago, IL 60637 USA

[2] Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Chem Program, New York, NY 10065 USA

[3] Massachusetts Gen Hosp, Dept Neurol, Genet & Aging Res Unit, Charlestown, MA 02129 USA

[4] TorreyPines Therapeut Inc, La Jolla, CA 92037 USA

[5] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92037 USA

来源：

NEURON | 2010年 / 67卷 / 05期

关键词：

IN-VIVO; INTRACELLULAR DOMAIN; A-BETA; NOTCH; INHIBITORS; COMPLEX; BRAIN; DIFFERENTIATION; PRESENILIN-1; PATHOLOGY;

D O I：

10.1016/j.neuron.2010.08.018

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Alzheimer's disease (AD) is characterized pathologically by the abundance of senile plaques and neurofibrillary tangles in the brain. We synthesized over 1200 novel gamma-secretase modulator (GSM) compounds that reduced A beta(42) levels without inhibiting epsilon-site cleavage of APP and Notch, the generation of the APP and Notch intracellular domains, respectively. These compounds also reduced A beta(40) levels while concomitantly elevating levels of A beta(38) and A beta(37). Immobilization of a potent GSM onto an agarose matrix quantitatively recovered Pen-2 and to a lesser degree PS-1 NTFs from cellular extracts. Moreover, oral administration (once daily) of another potent GSM to Tg 2576 transgenic AD mice displayed dose-responsive lowering of plasma and brain A beta(42); chronic daily administration led to significant reductions in both diffuse and neuritic plaques. These effects were observed in the absence of Notch-related changes (e.g., intestinal proliferation of goblet cells), which are commonly associated with repeated exposure to functional gamma-secretase inhibitors (GSIs).

引用

页码：769 / 780

页数：12

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