Abstract
β-Secretase (BACE) cleavage of amyloid precursor protein (APP) is one of the first steps in the production of amyloid β peptide Aβ42, the putative neurotoxic species in Alzheimer's disease. Recent studies have shown that BACE1 knockdown leads to hypomyelination, putatively caused by a decline in neuregulin (NRG)-1 processing. In this study, we have tested a potent cell-permeable BACE1 inhibitor (IC50 ∼ 30 nM) by administering it directly into the lateral ventricles of mice, expressing human wild-type (WT)-APP, to determine the consequences of BACE1 inhibition on brain APP and NRG-1 processing. BACE1 inhibition, in vivo, led to a significant dose- and time-dependent lowering of brain Aβ40 and Aβ42. BACE1 inhibition also led to a robust brain secreted (s)APPβ lowering that was accompanied by an increase in brain sAPPα levels. Although an increase in full-length NRG-1 levels was evident in 15-day-old BACE1 homozygous knockout (KO) (–/–) mice, in agreement with previous studies, this effect was also observed in 15-day-old heterozygous (+/–) mice, but it was not evident in 30-day-old and 2-year-old BACE1 KO (–/–) mice. Thus, BACE1 knockdown led to a transient decrease in NRG-1 processing in mice. Pharmacological inhibition of BACE1 in adult mice, which led to significant Aβ lowering, was without any significant effect on brain NRG-1 processing. Taken together, these results suggest that BACE1 is the major β-site cleavage enzyme for APP and that its inhibition can lower brain Aβ and redirect APP processing via the potentially nonamyloidogenic α-secretase pathway, without significantly altering NRG-1 processing.
Footnotes
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.130039.
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ABBREVIATIONS: AD, Alzheimer's disease; BACE, β-secretase; APP, amyloid precursor protein; sAPP, soluble amyloid precursor protein; CTF, C-terminal fragment; Aβ, amyloid β peptide (those mentioned herein consist of 40 or 42 amino acids); KO, knockout; NRG, neuregulin-1; P, postnatal day; WT, wild type; ELISA, enzyme-linked immunosorbent assay; AP, alkaline phosphatase; mkd, milligrams per kilogram per day; PBS, phosphate-buffered saline; MBP, myelin basic protein; HSD, honestly significant difference; NTF, N-terminal fragment; P-gp, P-glycoprotein; ANOVA, analysis of variance.
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↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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↵1 Current affiliation: Department of Oncology, GlaxoSmithKline, Collegeville, Pennsylvania.
- Received August 13, 2007.
- Accepted December 20, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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