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The novel beta-secretase inhibitor KMI-429 reduces amyloid beta peptide production in amyloid precursor protein transgenic and wild-type mice.
J Neurochem. 2006 Jan; 96(2):533-40.JN

Abstract

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 (Abeta), 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 Abeta 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 Abeta production in vivo in the soluble fraction compared with vehicle, but the level of Abeta in the insoluble fraction was unaffected. In contrast, an intrahippocampal injection of KMI-429 in wild-type mice remarkably reduced Abeta 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.

Authors+Show Affiliations

Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Tokyo, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16336629

Citation

Asai, Masashi, et al. "The Novel Beta-secretase Inhibitor KMI-429 Reduces Amyloid Beta Peptide Production in Amyloid Precursor Protein Transgenic and Wild-type Mice." Journal of Neurochemistry, vol. 96, no. 2, 2006, pp. 533-40.
Asai M, Hattori C, Iwata N, et al. The novel beta-secretase inhibitor KMI-429 reduces amyloid beta peptide production in amyloid precursor protein transgenic and wild-type mice. J Neurochem. 2006;96(2):533-40.
Asai, M., Hattori, C., Iwata, N., Saido, T. C., Sasagawa, N., Szabó, B., Hashimoto, Y., Maruyama, K., Tanuma, S., Kiso, Y., & Ishiura, S. (2006). The novel beta-secretase inhibitor KMI-429 reduces amyloid beta peptide production in amyloid precursor protein transgenic and wild-type mice. Journal of Neurochemistry, 96(2), 533-40.
Asai M, et al. The Novel Beta-secretase Inhibitor KMI-429 Reduces Amyloid Beta Peptide Production in Amyloid Precursor Protein Transgenic and Wild-type Mice. J Neurochem. 2006;96(2):533-40. PubMed PMID: 16336629.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The novel beta-secretase inhibitor KMI-429 reduces amyloid beta peptide production in amyloid precursor protein transgenic and wild-type mice. AU - Asai,Masashi, AU - Hattori,Chinatsu, AU - Iwata,Nobuhisa, AU - Saido,Takaomi C, AU - Sasagawa,Noboru, AU - Szabó,Beáta, AU - Hashimoto,Yasuhiro, AU - Maruyama,Kei, AU - Tanuma,Sei-ichi, AU - Kiso,Yoshiaki, AU - Ishiura,Shoichi, Y1 - 2005/12/08/ PY - 2005/12/13/pubmed PY - 2006/2/18/medline PY - 2005/12/13/entrez SP - 533 EP - 40 JF - Journal of neurochemistry JO - J Neurochem VL - 96 IS - 2 N2 - 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 (Abeta), 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 Abeta 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 Abeta production in vivo in the soluble fraction compared with vehicle, but the level of Abeta in the insoluble fraction was unaffected. In contrast, an intrahippocampal injection of KMI-429 in wild-type mice remarkably reduced Abeta 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. SN - 0022-3042 UR - https://www.unboundmedicine.com/medline/citation/16336629/The_novel_beta_secretase_inhibitor_KMI_429_reduces_amyloid_beta_peptide_production_in_amyloid_precursor_protein_transgenic_and_wild_type_mice_ L2 - https://doi.org/10.1111/j.1471-4159.2005.03576.x DB - PRIME DP - Unbound Medicine ER -