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

Abstract

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 0.3-1mg/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.

• Authors: Hideki Takahashi, Hiroaki Fukumoto, Ryouta Maeda, Jun Terauchi, Kaneyoshi Kato, Masaomi Miyamoto
• Journal: Brain research (Brain Res) Vol. 1361 Pg. 146-56 (Nov 18 2010) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 20849831 (Publication Type: Journal Article)
• Copyright: Copyright © 2010 Elsevier B.V. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Biphenyl Compounds
• Naphthalenes
• Peptide Fragments
• Synaptophysin
• TAK-070
• amyloid beta-protein (1-40)
• amyloid beta-protein (1-42)
• Amyloid Precursor Protein Secretases

Topics

• Administration, Oral
• Aging (drug effects, metabolism, psychology)
• Amyloid Precursor Protein Secretases (antagonists & inhibitors)
• Amyloid beta-Peptides (metabolism)
• Animals
• Biphenyl Compounds (administration & dosage, pharmacology)
• Brain (drug effects, metabolism)
• Cerebral Cortex (drug effects, metabolism)
• Dose-Response Relationship, Drug
• Enzyme-Linked Immunosorbent Assay
• Male
• Maze Learning (drug effects)
• Naphthalenes (administration & dosage, pharmacology)
• Neuropsychological Tests
• Peptide Fragments (metabolism)
• Rats
• Rats, Inbred F344
• Rats, Wistar
• Spatial Behavior (drug effects)
• Swimming
• Synaptophysin (metabolism)
• Treatment Outcome