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BACE1 inhibition reduces endogenous Abeta and alters APP processing in wild-type mice.
J Neurochem. 2006 Dec; 99(6):1555-63.JN

Abstract

Accumulation of amyloid beta peptide (Abeta) in brain is a hallmark of Alzheimer's disease (AD). Inhibition of beta-site amyloid precursor protein (APP)-cleaving enzyme-1 (BACE1), the enzyme that initiates Abeta production, and other Abeta-lowering strategies are commonly tested in transgenic mice overexpressing mutant APP. However, sporadic AD cases, which represent the majority of AD patients, are free from the mutation and do not necessarily have overproduction of APP. In addition, the commonly used Swedish mutant APP alters APP cleavage. Therefore, testing Abeta-lowering strategies in transgenic mice may not be optimal. In this study, we investigated the impact of BACE1 inhibition in non-transgenic mice with physiologically relevant APP expression. Existing Abeta ELISAs are either relatively insensitive to mouse Abeta or not specific to full-length Abeta. A newly developed ELISA detected a significant reduction of full-length soluble Abeta 1-40 in mice with the BACE1 homozygous gene deletion or BACE1 inhibitor treatment, while the level of x-40 Abeta was moderately reduced due to detection of non-full-length Abeta and compensatory activation of alpha-secretase. These results confirmed the feasibility of Abeta reduction through BACE1 inhibition under physiological conditions. Studies using our new ELISA in non-transgenic mice provide more accurate evaluation of Abeta-reducing strategies than was previously feasible.

Authors+Show Affiliations

Pain & Neurology, Discovery Research Laboratories, Shionogi Co. Ltd, Shiga, 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 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, N.I.H., Extramural

Language

eng

PubMed ID

17083447

Citation

Nishitomi, Kouhei, et al. "BACE1 Inhibition Reduces Endogenous Abeta and Alters APP Processing in Wild-type Mice." Journal of Neurochemistry, vol. 99, no. 6, 2006, pp. 1555-63.
Nishitomi K, Sakaguchi G, Horikoshi Y, et al. BACE1 inhibition reduces endogenous Abeta and alters APP processing in wild-type mice. J Neurochem. 2006;99(6):1555-63.
Nishitomi, K., Sakaguchi, G., Horikoshi, Y., Gray, A. J., Maeda, M., Hirata-Fukae, C., Becker, A. G., Hosono, M., Sakaguchi, I., Minami, S. S., Nakajima, Y., Li, H. F., Takeyama, C., Kihara, T., Ota, A., Wong, P. C., Aisen, P. S., Kato, A., Kinoshita, N., & Matsuoka, Y. (2006). BACE1 inhibition reduces endogenous Abeta and alters APP processing in wild-type mice. Journal of Neurochemistry, 99(6), 1555-63.
Nishitomi K, et al. BACE1 Inhibition Reduces Endogenous Abeta and Alters APP Processing in Wild-type Mice. J Neurochem. 2006;99(6):1555-63. PubMed PMID: 17083447.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - BACE1 inhibition reduces endogenous Abeta and alters APP processing in wild-type mice. AU - Nishitomi,Kouhei, AU - Sakaguchi,Gaku, AU - Horikoshi,Yuko, AU - Gray,Audrey J, AU - Maeda,Masahiro, AU - Hirata-Fukae,Chiho, AU - Becker,Amanda G, AU - Hosono,Motoko, AU - Sakaguchi,Isako, AU - Minami,S Sakura, AU - Nakajima,Yoshihiro, AU - Li,Hui-Fang, AU - Takeyama,Chie, AU - Kihara,Tsuyoshi, AU - Ota,Akinobu, AU - Wong,Philip C, AU - Aisen,Paul S, AU - Kato,Akira, AU - Kinoshita,Noriaki, AU - Matsuoka,Yasuji, Y1 - 2006/11/02/ PY - 2006/11/7/pubmed PY - 2007/2/16/medline PY - 2006/11/7/entrez SP - 1555 EP - 63 JF - Journal of neurochemistry JO - J. Neurochem. VL - 99 IS - 6 N2 - Accumulation of amyloid beta peptide (Abeta) in brain is a hallmark of Alzheimer's disease (AD). Inhibition of beta-site amyloid precursor protein (APP)-cleaving enzyme-1 (BACE1), the enzyme that initiates Abeta production, and other Abeta-lowering strategies are commonly tested in transgenic mice overexpressing mutant APP. However, sporadic AD cases, which represent the majority of AD patients, are free from the mutation and do not necessarily have overproduction of APP. In addition, the commonly used Swedish mutant APP alters APP cleavage. Therefore, testing Abeta-lowering strategies in transgenic mice may not be optimal. In this study, we investigated the impact of BACE1 inhibition in non-transgenic mice with physiologically relevant APP expression. Existing Abeta ELISAs are either relatively insensitive to mouse Abeta or not specific to full-length Abeta. A newly developed ELISA detected a significant reduction of full-length soluble Abeta 1-40 in mice with the BACE1 homozygous gene deletion or BACE1 inhibitor treatment, while the level of x-40 Abeta was moderately reduced due to detection of non-full-length Abeta and compensatory activation of alpha-secretase. These results confirmed the feasibility of Abeta reduction through BACE1 inhibition under physiological conditions. Studies using our new ELISA in non-transgenic mice provide more accurate evaluation of Abeta-reducing strategies than was previously feasible. SN - 0022-3042 UR - https://www.unboundmedicine.com/medline/citation/17083447/BACE1_inhibition_reduces_endogenous_Abeta_and_alters_APP_processing_in_wild_type_mice_ L2 - https://doi.org/10.1111/j.1471-4159.2006.04178.x DB - PRIME DP - Unbound Medicine ER -