Journal
JOURNAL OF NEUROSCIENCE
Volume 30, Issue 33, Pages 11157-11166Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2884-10.2010
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We discovered a nonpeptidic compound, TAK-070, that inhibited BACE1, a rate-limiting protease for the generation of A beta 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 A beta, increased that of neurotrophic sAPP alpha by similar to 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 A beta deposition by similar to 60%, preserving the pharmacological efficacy on soluble A beta and sAPP alpha 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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