A noncompetitive BACE1 inhibitor TAK-070 ameliorates Abeta pathology and behavioral deficits in a mouse model of Alzheimer's disease

  • J Neurosci. 2010 Aug 18;30(33):11157-66. doi: 10.1523/JNEUROSCI.2884-10.2010.
Hiroaki Fukumoto  1 ,  Hideki Takahashi ,  Naoki Tarui ,  Junji Matsui ,  Taisuke Tomita ,  Mitsuhiro Hirode ,  Masumi Sagayama ,  Ryouta Maeda ,  Makiko Kawamoto ,  Kazuko Hirai ,  Jun Terauchi ,  Yasufumi Sakura ,  Mitsuru Kakihana ,  Kaneyoshi Kato ,  Takeshi Iwatsubo ,  Masaomi Miyamoto
Affiliations
  • 1. Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Yodogawa-ku, Osaka 532-8686, Japan. [email protected]
PMID: 20720123 DOI: 10.1523/JNEUROSCI.2884-10.2010
Abstract

We discovered a nonpeptidic compound, TAK-070, that inhibited BACE1, a rate-limiting protease for the generation of Abeta 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 Abeta, increased that of neurotrophic sAPPalpha by approximately 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 Abeta deposition by approximately 60%, preserving the pharmacological efficacy on soluble Abeta and sAPPalpha levels. These results support the feasibility of BACE1 inhibition with a noncompetitive inhibitor as disease-modifying as well as symptomatic therapy for AD.

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