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High beta-secretase activity elicits neurodegeneration in transgenic mice despite reductions in amyloid-beta levels: implications for the treatment of Alzheimer disease.
J Biol Chem. 2005 Sep 23; 280(38):32957-67.JB

Abstract

Amyloid-beta peptides (Abeta) are widely presumed to play a causal role in Alzheimer disease. Release of Abeta from the amyloid precursor protein (APP) requires proteolysis by the beta-site APP-cleaving enzyme (BACE1). Although increased BACE1 activity in Alzheimer disease brains and human (h) BACE1 transgenic (tg) mice results in altered APP cleavage, the contribution of these molecular alterations to neurodegeneration is unclear. We therefore used the murine Thy1 promoter to express high levels of hBACE1, with or without hAPP, in neurons of tg mice. Compared with hAPP mice, hBACE1/hAPP doubly tg mice had increased levels of APP C-terminal fragments (C89, C83) and decreased levels of full-length APP and Abeta. In contrast to non-tg controls and hAPP mice, hBACE1 mice and hBACE1/hAPP mice showed degeneration of neurons in the neocortex and hippocampus and degradation of myelin. Neurological deficits were also more severe in hBACE1 and hBACE1/hAPP mice than in hAPP mice. These results demonstrate that high levels of BACE1 activity are sufficient to elicit neurodegeneration and neurological decline in vivo. This pathogenic pathway involves the accumulation of APP C-terminal fragments but does not depend on increased production of human Abeta. Thus, inhibiting BACE1 may block not only Abeta-dependent but also Abeta-independent pathogenic mechanisms.

Authors+Show Affiliations

Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, California 92093-0624, USA.No 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
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

16027115

Citation

Rockenstein, Edward, et al. "High Beta-secretase Activity Elicits Neurodegeneration in Transgenic Mice Despite Reductions in Amyloid-beta Levels: Implications for the Treatment of Alzheimer Disease." The Journal of Biological Chemistry, vol. 280, no. 38, 2005, pp. 32957-67.
Rockenstein E, Mante M, Alford M, et al. High beta-secretase activity elicits neurodegeneration in transgenic mice despite reductions in amyloid-beta levels: implications for the treatment of Alzheimer disease. J Biol Chem. 2005;280(38):32957-67.
Rockenstein, E., Mante, M., Alford, M., Adame, A., Crews, L., Hashimoto, M., Esposito, L., Mucke, L., & Masliah, E. (2005). High beta-secretase activity elicits neurodegeneration in transgenic mice despite reductions in amyloid-beta levels: implications for the treatment of Alzheimer disease. The Journal of Biological Chemistry, 280(38), 32957-67.
Rockenstein E, et al. High Beta-secretase Activity Elicits Neurodegeneration in Transgenic Mice Despite Reductions in Amyloid-beta Levels: Implications for the Treatment of Alzheimer Disease. J Biol Chem. 2005 Sep 23;280(38):32957-67. PubMed PMID: 16027115.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - High beta-secretase activity elicits neurodegeneration in transgenic mice despite reductions in amyloid-beta levels: implications for the treatment of Alzheimer disease. AU - Rockenstein,Edward, AU - Mante,Michael, AU - Alford,Michael, AU - Adame,Anthony, AU - Crews,Leslie, AU - Hashimoto,Makoto, AU - Esposito,Luke, AU - Mucke,Lennart, AU - Masliah,Eliezer, Y1 - 2005/07/15/ PY - 2005/7/20/pubmed PY - 2005/12/13/medline PY - 2005/7/20/entrez SP - 32957 EP - 67 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 280 IS - 38 N2 - Amyloid-beta peptides (Abeta) are widely presumed to play a causal role in Alzheimer disease. Release of Abeta from the amyloid precursor protein (APP) requires proteolysis by the beta-site APP-cleaving enzyme (BACE1). Although increased BACE1 activity in Alzheimer disease brains and human (h) BACE1 transgenic (tg) mice results in altered APP cleavage, the contribution of these molecular alterations to neurodegeneration is unclear. We therefore used the murine Thy1 promoter to express high levels of hBACE1, with or without hAPP, in neurons of tg mice. Compared with hAPP mice, hBACE1/hAPP doubly tg mice had increased levels of APP C-terminal fragments (C89, C83) and decreased levels of full-length APP and Abeta. In contrast to non-tg controls and hAPP mice, hBACE1 mice and hBACE1/hAPP mice showed degeneration of neurons in the neocortex and hippocampus and degradation of myelin. Neurological deficits were also more severe in hBACE1 and hBACE1/hAPP mice than in hAPP mice. These results demonstrate that high levels of BACE1 activity are sufficient to elicit neurodegeneration and neurological decline in vivo. This pathogenic pathway involves the accumulation of APP C-terminal fragments but does not depend on increased production of human Abeta. Thus, inhibiting BACE1 may block not only Abeta-dependent but also Abeta-independent pathogenic mechanisms. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/16027115/High_beta_secretase_activity_elicits_neurodegeneration_in_transgenic_mice_despite_reductions_in_amyloid_beta_levels:_implications_for_the_treatment_of_Alzheimer_disease_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=16027115 DB - PRIME DP - Unbound Medicine ER -