A Noncompetitive BACE1 Inhibitor TAK-070 Ameliorates Aβ Pathology and Behavioral Deficits in a Mouse Model of Alzheimer's Disease
| Autor: | Junji Matsui, Makiko Kawamoto, Jun Terauchi, Mitsuhiro Hirode, Mitsuru Kakihana, Naoki Tarui, Hideki Takahashi, Masaomi Miyamoto, Masumi Sagayama, Kazuko Hirai, Kaneyoshi Kato, Hiroaki Fukumoto, Yasufumi Sakura, Ryouta Maeda, Takeshi Iwatsubo, Taisuke Tomita |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Genetically modified mouse
Male medicine.medical_treatment Transgene Mice Transgenic Receptors Cell Surface Pharmacology Naphthalenes Amyloid beta-Protein Precursor Mice Random Allocation Non-competitive inhibition Oral administration Alzheimer Disease Cell Line Tumor mental disorders Medicine Animals Aspartic Acid Endopeptidases Humans Enzyme Inhibitors Receptor Maze Learning Protease Amyloid beta-Peptides biology business.industry General Neuroscience Biphenyl Compounds Brain Recognition Psychology Articles Protease Nexins Disease Models Animal Treatment Outcome Cell culture biology.protein Feasibility Studies Female Amyloid Precursor Protein Secretases business Cognition Disorders Neuroscience Neurotrophin |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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