Ameliorative effects of a non-competitive BACE1 inhibitor TAK-070 on A beta peptide levels and impaired learning behavior in aged rats

作者：Takahashi Hideki^*; Fukumoto Hiroaki; Maeda Ryouta; Terauchi Jun; Kato Kaneyoshi; Miyamoto Masaomi

来源：Brain Research, 2010, 1361: 146-156.

DOI：10.1016/j.brainres.2010.09.032

• TAK-070
• A beta
• BACE
• Alzheimer's disease
• Aged rat
• Water maze

We examined the effects of TAK-070, a novel non-competitive p-secretase (BACE1) inhibitor, on the levels of A beta peptides and behavioral deficits in rats. TAK-070 reduced soluble A beta 40 and A beta 42 levels of the cerebral cortex in a time- and dose-dependent manner in young rats. We found that the insoluble A beta 42 content increased significantly with aging from 22 months old without changing A beta 40 content. TAK-070 normalized the A beta 42 levels to those in young rats when they were fed chow containing TAK-070 starting at 19 months old for 6.5 months. Repeated administration of TAK-070 to aged rats for 2 weeks ameliorated the impaired spatial learning in the Morris water maze task and reduced the levels of soluble and insoluble A beta peptides at doses of 0.3-1 mg/kg, (p.o.). Interestingly, TAK-070 significantly recovered the reduced brain synaptophysin levels in aged rats to those in young rats. Our findings support the idea that partial inhibition of BACE1 by TAK-070 exerts symptomatic as well as disease-modifying effects for the treatment of Alzheimer's disease.

• 出版日期2010-11-18