γ-Secretase Heterogeneity in the Aph1 Subunit: Relevance for Alzheimer's Disease

被引：218

作者：

Serneels, Lutgarde ^{[1
,2
]}

Van Biervliet, Jerome ^{[1
,2
]}

Craessaerts, Katleen ^{[1
,2
]}

Dejaegere, Tim ^{[1
,2
]}

Horre, Katrien ^{[1
,2
]}

Van Houtvin, Tine ^{[1
,2
]}

Esselmann, Hermann ^{[3
,4
]}

Paul, Sabine ^{[3
,4
]}

Schaefer, Martin K. ^{[5
]}

Berezovska, Oksana ^{[6
]}

Hyman, Bradley T. ^{[6
]}

Sprangers, Ben ^{[7
]}

Sciot, Raf ^{[8
]}

Moons, Lieve ^{[9
]}

Jucker, Mathias ^{[10
]}

Yang, Zhixiang ^{[11
]}

May, Patrick C. ^{[11
]}

Karran, Eric ^{[12
]}

Wiltfang, Jens ^{[3
,4
]}

D'Hooge, Rudi ^{[13
]}

De Strooper, Bart ^{[1
,2
]}

机构：

[1] Katholieke Univ Leuven VIB, Dept Mol & Dev Genet, B-3000 Louvain, Belgium

[2] Katholieke Univ Leuven, Ctr Human Genet, B-3000 Louvain, Belgium

[3] Univ Erlangen Nurnberg, Dept Psychiat & Psychotherapy, D-91054 Erlangen, Germany

[4] Univ Duisburg Essen, Rhine State Hosp Essen, Dept Psychiat & Psychotherapy, D-45147 Essen, Germany

[5] Univ Marburg, Inst Anat & Cell Biol, Dept Mol Neurosci, D-35032 Marburg, Germany

[6] Harvard Univ, Sch Med, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Disorders, Charlestown, MA 02129 USA

[7] Katholieke Univ Leuven, Lab Expt Transplantat, B-3000 Louvain, Belgium

[8] Katholieke Univ Leuven, Lab Morphol & Mol Pathol, B-3000 Louvain, Belgium

[9] Katholieke Univ Leuven, Lab Neural Circuit Dev & Regenerat, Dept Biol, B-3000 Louvain, Belgium

[10] Univ Tubingen, Dept Cellular Neurol, Hertie Inst Clin Brain Res, D-72076 Tubingen, Germany

[11] Eli Lilly & Co, Lilly Res Labs, Neurosci Discovery Res, Indianapolis, IN 46285 USA

[12] Lilly Res Ctr Ltd, Windlesham GU20 6PH, Surrey, England

[13] Katholieke Univ Leuven, Dept Psychol, Lab Biol Psychol, B-3000 Louvain, Belgium

来源：

SCIENCE | 2009年 / 324卷 / 5927期

关键词：

AMYLOID PRECURSOR PROTEIN; MODERATE REDUCTION; TRANSGENIC MODEL; IN-VIVO; MICE; PRESENILIN-1; COMPLEXES; DEFICIENCY; EXPRESSION; CLEAVAGE;

D O I：

10.1126/science.1171176

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The gamma-secretase complex plays a role in Alzheimer's disease and cancer progression. The development of clinically useful inhibitors, however, is complicated by the role of the gamma-secretase complex in regulated intramembrane proteolysis of Notch and other essential proteins. Different gamma-secretase complexes containing different Presenilin or Aph1 protein subunits are present in various tissues. Here we show that these complexes have heterogeneous biochemical and physiological properties. Specific inactivation of the Aph1B gamma-secretase in a mouse Alzheimer's disease model led to improvements of Alzheimer's disease-relevant phenotypic features without any Notch-related side effects. The Aph1B complex contributes to total gamma-secretase activity in the human brain, and thus specific targeting of Aph1B-containing gamma-secretase complexes may help generate less toxic therapies for Alzheimer's disease.

引用

页码：639 / 642

页数：4

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