Alzheimer's Disease: Presenilin 2-Sparing γ-Secretase Inhibition Is a Tolerable Aβ Peptide-Lowering Strategy

被引：37

作者：

Borgegard, Tomas ^{[2
]}

Gustavsson, Susanne ^{[2
]}

Nilsson, Charlotte ^{[2
]}

Parpal, Santiago ^{[2
]}

Klintenberg, Rebecka ^{[2
]}

Berg, Anna-Lena ^{[2
]}

Rosqvist, Susanne ^{[2
]}

Serneels, Lutgarde ^{[3
,4
,6
]}

Svensson, Samuel ^{[1
,2
,10
]}

Olsson, Fredrik ^{[2
]}

Jin, Shaobo ^{[5
]}

Yan, Hongmei ^{[2
]}

Wanngren, Johanna ^{[7
]}

Jureus, Anders ^{[2
]}

Ridderstad-Wollberg, Anna ^{[2
]}

Wollberg, Patrik ^{[2
]}

Stockling, Kenneth ^{[2
]}

Karlstrom, Helena ^{[7
]}

Malmberg, Asa ^{[2
]}

Lund, Johan ^{[2
]}

Arvidsson, Per I. ^{[2
,8
,9
]}

De Strooper, Bart ^{[3
,4
,6
]}

Lendahl, Urban ^{[5
]}

Lundkvist, Johan ^{[1
,2
,7
]}

机构：

[1] Alzacure Fdn, SE-12064 Stockholm, Sweden

[2] AstraZeneca, CNS & Pain Innovat Med, SE-15185 Sodertalje, Sweden

[3] Univ Louvain, Ctr Human Genet, B-3000 Louvain, Belgium

[4] Univ Louvain, LIND, B-3000 Louvain, Belgium

[5] Karolinska Inst, Dept Cell & Mol Biol, SE-17177 Stockholm, Sweden

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

[7] Karolinska Inst, Dept Neurobiol Caring Sci & Soc, KI Alzheimer Dis Res Ctr, SE-14186 Stockholm, Sweden

[8] Uppsala Univ, Uppsala Biomed Ctr, Dept Med Chem, SE-75123 Uppsala, Sweden

[9] Univ KwaZulu Natal, Sch Pharm & Pharmacol, ZA-4000 Durban, South Africa

[10] Linkoping Univ, Dept Pharmacol, S-58183 Linkoping, Sweden

来源：

JOURNAL OF NEUROSCIENCE | 2012年 / 32卷 / 48期

基金：

瑞典研究理事会;

关键词：

GENES; IDENTIFICATION; MODULATION; COMPLEXES; CLEAVAGE; POTENT; DOMAIN; CELLS;

D O I：

10.1523/JNEUROSCI.1451-12.2012

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

gamma-Secretase inhibition represents a major therapeutic strategy for lowering amyloid beta (A beta) peptide production in Alzheimer's disease (AD). Progress toward clinical use of gamma-secretase inhibitors has, however, been hampered due to mechanism-based adverse events, primarily related to impairment of Notch signaling. The gamma-secretase inhibitor MRK-560 represents an exception as it is largely tolerable in vivo despite displaying only a small selectivity between A beta production and Notch signaling in vitro. In exploring the molecular basis for the observed tolerability, we show that MRK-560 displays a strong preference for the presenilin 1(PS1) over PS2 subclass of gamma-secretases and is tolerable in wild-type mice but causes dose-dependent Notch-related side effect in PS2-deficient mice at drug exposure levels resulting in a substantial decrease in brain A beta levels. This demonstrates that PS2 plays an important role in mediating essential Notch signaling in several peripheral organs during pharmacological inhibition of PS1 and provide preclinical in vivo proof of concept for PS2-sparing inhibition as a novel, tolerable and efficacious gamma-secretase targeting strategy for AD.

引用

页码：17297 / 17305

页数：9

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