Lessons from a Failed γ-Secretase Alzheimer Trial

被引：224

作者：

De Strooper, Bart ^{[1
,2
,3
,4
]}

机构：

[1] VIB Ctr Biol Dis, B-3000 Louvain, Belgium

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

[3] Univ Leuven, Leuven Inst Neurodegenerat disorders, B-3000 Louvain, Belgium

[4] UCL, UCL Inst Neurol, London WC1N 1PJ, England

来源：

CELL | 2014年 / 159卷 / 04期

基金：

欧洲研究理事会;

关键词：

AMYLOID PRECURSOR PROTEIN; SIGNAL PEPTIDE PEPTIDASE; BETA-PEPTIDE; SYNAPTIC PLASTICITY; ASPARTIC PROTEASE; DISEASE; PRESENILIN; INHIBITOR; MICE; SEMAGACESTAT;

D O I：

10.1016/j.cell.2014.10.016

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

gamma-Secretase proteases have been associated with pathology in Alzheimer disease (AD), but we are just beginning to understand their basic mechanisms and physiological roles. A negative drug trial with a broad spectrum gamma-secretase inhibitor in AD patients has severely dampened enthusiasm for the potential of pursuing gamma-secretase research therapeutically. This pessimism is unwarranted: analysis of available information presented here demonstrates significant confounds for interpreting the outcome of the trial and argues that the major lessons pertain to broad knowledge gaps that are imperative to fill.

引用

页码：721 / 726

页数：6

共 46 条

[1] Not(ch) just development: Notch signalling in the adult brain [J].

Ables, Jessica L. ;

Breunig, Joshua J. ;

Eisch, Amelia J. ;

Rakic, Pasko .

NATURE REVIEWS NEUROSCIENCE, 2011, 12 (05) :269-283

[2] Activity-Induced Notch Signaling in Neurons Requires Arc/Arg3.1 and Is Essential for Synaptic Plasticity in Hippocampal Networks [J].

Alberi, Lavinia ;

Liu, Shuxi ;

Wang, Yue ;

Badie, Ramy ;

Smith-Hicks, Constance ;

Wu, Jing ;

Pierfelice, Tarran J. ;

Abazyan, Bagrat ;

Mattson, Mark P. ;

Kuhl, Dietmar ;

Pletnikov, Mikhail ;

Worley, Paul F. ;

Gaiano, Nicholas .

NEURON, 2011, 69 (03) :437-444

[3] RETRACTED: Functional and Topological Analysis of Pen-2, the Fourth Subunit of the γ-Secretase Complex (Withdrawn Publication. See vol. 299, 2023) (Retracted Article) [J].

Bammens, Leen ;

Chavez-Gutierrez, Lucia ;

Tolia, Alexandra ;

Zwijsen, An ;

De Strooper, Bart .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286 (14) :12271-12282

[4] A γ-Secretase Inhibitor Decreases Amyloid-β Production in the Central Nervous System [J].

Bateman, Randall J. ;

Siemers, Eric R. ;

Mawuenyega, Kwasi G. ;

Wen, Guolin ;

Browning, Karen R. ;

Sigurdson, Wendy C. ;

Yarasheski, Kevin E. ;

Friedrich, Stuart W. ;

DeMattos, Ronald B. ;

May, Patrick C. ;

Paul, Steven M. ;

Holtzman, David M. .

ANNALS OF NEUROLOGY, 2009, 66 (01) :48-54

[5] Alzheimer's Disease: Presenilin 2-Sparing γ-Secretase Inhibition Is a Tolerable Aβ Peptide-Lowering Strategy [J].

Borgegard, Tomas ;

Gustavsson, Susanne ;

Nilsson, Charlotte ;

Parpal, Santiago ;

Klintenberg, Rebecka ;

Berg, Anna-Lena ;

Rosqvist, Susanne ;

Serneels, Lutgarde ;

Svensson, Samuel ;

Olsson, Fredrik ;

Jin, Shaobo ;

Yan, Hongmei ;

Wanngren, Johanna ;

Jureus, Anders ;

Ridderstad-Wollberg, Anna ;

Wollberg, Patrik ;

Stockling, Kenneth ;

Karlstrom, Helena ;

Malmberg, Asa ;

Lund, Johan ;

Arvidsson, Per I. ;

De Strooper, Bart ;

Lendahl, Urban ;

Lundkvist, Johan .

JOURNAL OF NEUROSCIENCE, 2012, 32 (48) :17297-17305

[6] The mechanism of γ-Secretase dysfunction in familial Alzheimer disease [J].

Chavez-Gutierrez, Lucia ;

Bammens, Leen ;

Benilova, Iryna ;

Vandersteen, Annelies ;

Benurwar, Manasi ;

Borgers, Marianne ;

Lismont, Sam ;

Zhou, Lujia ;

Van Cleynenbreugel, Simon ;

Esselmann, Hermann ;

Wiltfang, Jens ;

Serneels, Lutgarde ;

Karran, Eric ;

Gijsen, Harrie ;

Schymkowitz, Joost ;

Rousseau, Frederic ;

Broersen, Kerensa ;

De Strooper, Bart .

EMBO JOURNAL, 2012, 31 (10) :2261-2274

[7] BMS-708,163 Targets Presenilin and Lacks Notch-Sparing Activity [J].

Crump, Christina J. ;

Castro, Suita V. ;

Wang, Feng ;

Pozdnyakov, Nikolay ;

Ballard, T. Eric ;

Sisodia, Sangram S. ;

Bales, Kelly R. ;

Johnson, Douglas S. ;

Li, Yue-Ming .

BIOCHEMISTRY, 2012, 51 (37) :7209-7211

[8] Aph-1, Pen-2, and nicastrin with presenilin generate an active γ-secretase complex [J].

De Strooper, B .

NEURON, 2003, 38 (01) :9-12

[9] Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein [J].

De Strooper, B ;

Saftig, P ;

Craessaerts, K ;

Vanderstichele, H ;

Guhde, G ;

Annaert, W ;

Von Figura, K ;

Van Leuven, F .

NATURE, 1998, 391 (6665) :387-390

[10] Spike bursts increase amyloid-β 40/42 ratio by inducing a presenilin-1 conformational change [J].

Dolev, Iftach ;

Fogel, Hilla ;

Milshtein, Hila ;

Berdichevsky, Yevgeny ;

Lipstein, Noa ;

Brose, Nils ;

Gazit, Neta ;

Slutsky, Inna .

NATURE NEUROSCIENCE, 2013, 16 (05) :587-+

← 1 2 3 4 5 →