Normal brain development in PS1 hypomorphic mice with markedly reduced γ-secretase cleavage of βAPP

被引：36

作者：

Rozmahel, R

Huang, J

Chen, F

Liang, Y

Nguyen, V

Ikeda, M

Levesque, G

Yu, G

Nishimura, M

Mathews, P

Schmidt, SD

Mercken, M

Bergeron, C

Westaway, D

St George-Hyslop, P

机构：

[1] Univ Toronto, Dept Lab Med & Pathobiol, Ctr Res Neurogenerat Dis, Toronto, ON M5S 1A1, Canada

[2] Univ Toronto, Dept Pharmacol, Ctr Res Neurogenerat Dis, Toronto, ON M5S 1A1, Canada

[3] Univ Toronto, Dept Med, Ctr Res Neurogenerat Dis, Toronto, ON M5S 1A1, Canada

[4] Hosp Sick Children, Dept Genet, Toronto, ON M5G 1X8, Canada

[5] Toronto Western Hosp, Univ Hlth Network, Dept Med, Div Neurol, Toronto, ON M5T 2S8, Canada

[6] Toronto Western Hosp, Univ Hlth Network, Dept Pathol, Toronto, ON M5T 2S8, Canada

[7] Univ Sherbrooke, Dept Biochem, Sherbrooke, PQ J1K 2R1, Canada

[8] NYU, Med Ctr, Nathan Kline Inst, Ctr Dementia Res, Orangeburg, NY 10962 USA

[9] Janssen Res Fdn, B-2340 Beerse, Belgium

来源：

NEUROBIOLOGY OF AGING | 2002年 / 23卷 / 02期

基金：

加拿大健康研究院;

关键词：

presenilin; beta-amyloid precursor protein; Notch signaling; Alzheimer's Disease; gamma-secretase; mouse model; gene targeting;

D O I：

10.1016/S0197-4580(01)00267-6

中图分类号：

R592 [老年病学]; C [社会科学总论];

学科分类号：

03 ; 0303 ; 100203 ;

摘要：

Presenilin 1-null mice die at birth from brain and skeletal developmental deformities due to disrupted Notch signaling. Presenilin 1-null mice also have severely reduced gamma-secretase cleavage of betaAPP. The assumption has been that facilitation of Notch signaling and betaAPP processing by presenifin 1 are analogous functions. Here we describe a presenilin 1-targetted mouse model that expresses extremely low levels (similar to1% of normal) of mutant PS1-M146L. Homozygous mice have significantly reduced viability due to a Notch-like phenotype. The animals that survive have severe axial skeletal deformities and markedly diminished gamma-secretase activity and accumulation of betaAPP-C100, but no obvious abnormalities in brain development. These results suggest that, in mice, a marked reduction of PS1-facilitated gamma-secretase activity is not detrimental to normal brain development. (C) 2002 Elsevier Science Inc. All rights reserved.

引用

页码：187 / 194

页数：8

共 27 条

[1] alpha-secretase-derived product of beta-amyloid precursor protein is decreased by presenilin 1 mutations linked to familial Alzheimer's disease [J].