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

We examined the effects of TAK-070, a novel non-competitive β-secretase (BACE1) inhibitor, on the levels of Aβ peptides and behavioral deficits in rats. TAK-070 reduced soluble Aβ40 and Aβ42 levels of the cerebral cortex in a time- and dose-dependent manner in young rats. We found that the insoluble Aβ42 content increased significantly with aging from 22 months old without changing Aβ40 content. TAK-070 normalized the Aβ42 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 Aβ 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.

Research Highlights► No BACE inhibitors except TAK-070 describe biochemical/behavioral effects in rats. ► First report that insoluble Aβ42 level increased with aging in rat brain. ► TAK-070 normalized the increased brain Aβ levels to those of normal. ► TAK-070 ameliorated the impaired cognitive deficits in aged rat model.