A Noncompetitive BACE1 Inhibitor TAK-070 Ameliorates Aβ Pathology and Behavioral Deficits in a Mouse Model of Alzheimer's Disease

被引：112

作者：

Fukumoto, Hiroaki ^{[1
]}

Takahashi, Hideki ^{[1
]}

Tarui, Naoki ^{[1
]}

Matsui, Junji ^{[1
]}

Tomita, Taisuke ^{[2
]}

Hirode, Mitsuhiro ^{[1
]}

Sagayama, Masumi ^{[1
]}

Maeda, Ryouta ^{[1
]}

Kawamoto, Makiko ^{[1
]}

Hirai, Kazuko ^{[1
]}

Terauchi, Jun ^{[1
]}

Sakura, Yasufumi ^{[1
]}

Kakihana, Mitsuru ^{[1
]}

Kato, Kaneyoshi ^{[1
]}

Iwatsubo, Takeshi ^{[2
,3
]}

Miyamoto, Masaomi ^{[1
]}

机构：

[1] Takeda Pharmaceut Co Ltd, Div Pharmaceut Res, Yodogawa Ku, Osaka 5328686, Japan

[2] Univ Tokyo, Grad Sch Pharmaceut Sci, Dept Neuropathol & Neurosci, Bunkyo Ku, Tokyo 1130033, Japan

[3] Univ Tokyo, Grad Sch Med, Dept Neuropathol, Bunkyo Ku, Tokyo 1130033, Japan

来源：

JOURNAL OF NEUROSCIENCE | 2010年 / 30卷 / 33期

关键词：

AMYLOID PRECURSOR PROTEIN; MEMORY DEFICITS; ALPHA-SECRETASE; TRANSGENIC MICE; IN-VIVO; CLEAVING ENZYME; BRAIN; APP; CLEAVAGE; PRESENILIN-1;

D O I：

10.1523/JNEUROSCI.2884-10.2010

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

We discovered a nonpeptidic compound, TAK-070, that inhibited BACE1, a rate-limiting protease for the generation of A beta peptides that are considered causative for Alzheimer's disease (AD), in a noncompetitive manner. TAK-070 bound to full-length BACE1, but not to truncated BACE1 lacking the transmembrane domain. Short-term oral administration of TAK-070 decreased the brain levels of soluble A beta, increased that of neurotrophic sAPP alpha by similar to 20%, and normalized the behavioral impairments in cognitive tests in Tg2576 mice, an APP transgenic mouse model of AD. Six-month chronic treatment decreased cerebral A beta deposition by similar to 60%, preserving the pharmacological efficacy on soluble A beta and sAPP alpha levels. These results support the feasibility of BACE1 inhibition with a noncompetitive inhibitor as disease-modifying as well as symptomatic therapy for AD.

引用

页码：11157 / 11166

页数：10

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