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Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. The major component of the plaques, amyloid [beta] peptide (A[beta]), is generated from amyloid precursor protein (APP) by [beta]- and [gamma]-secretase-mediated cleavage. Because [beta]-secretase/beta-site APP cleaving enzyme 1 (BACE1) knockout mice produce much less A[beta] and grow normally, a [beta]-secretase inhibitor is thought to be one of the most attractive targets for the development of therapeutic interventions for AD without apparent side-effects. Here, we report the in vivo inhibitory effects of a novel [beta]-secretase inhibitor, KMI-429, a transition-state mimic, which effectively inhibits [beta]-secretase activity in cultured cells in a dose-dependent manner. We injected KMI-429 into the hippocampus of APP transgenic mice. KMI-429 significantly reduced A[beta] production in vivo in the soluble fraction compared with vehicle, but the level of A[beta] in the insoluble fraction was unaffected. In contrast, an intrahippocampal injection of KMI-429 in wild-type mice remarkably reduced A[beta] production in both the soluble and insoluble fractions. Our results indicate that the [beta]-secretase inhibitor KMI-429 is a promising candidate for the treatment of AD.

(C) 2006 International Society for Neurochemistry