title: In vivo beta-secretase 1 inhibition leads to brain Abeta lowering and increased alpha-secretase processing of amyloid precursor protein without effect on neuregulin-1.
abstract: beta-Secretase (BACE) cleavage of amyloid precursor protein (APP) is one of the first steps in the production of amyloid beta peptide Abeta42, 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 (IC(50) approximately 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 Abeta40 and Abeta42. BACE1 inhibition also led to a robust brain secreted (s)APPbeta lowering that was accompanied by an increase in brain sAPPalpha 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 Abeta lowering, was without any significant effect on brain NRG-1 processing. Taken together, these results suggest that BACE1 is the major beta-site cleavage enzyme for APP and that its inhibition can lower brain Abeta and redirect APP processing via the potentially nonamyloidogenic alpha-secretase pathway, without significantly altering NRG-1 processing.
authors.affiliation: Department of Alzheimer's Research, WP 26A-2000, Merck Research Laboratories, 770, Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: Sethu
authors.initials: S
authors.lastname: Sankaranarayanan
authors.forename: Eric A
authors.initials: EA
authors.lastname: Price
authors.forename: Guoxin
authors.initials: G
authors.lastname: Wu
authors.forename: Ming-Chih
authors.initials: MC
authors.lastname: Crouthamel
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Shi
authors.forename: Katherine
authors.initials: K
authors.lastname: Tugusheva
authors.forename: Keala X
authors.initials: KX
authors.lastname: Tyler
authors.forename: Jason
authors.initials: J
authors.lastname: Kahana
authors.forename: Joan
authors.initials: J
authors.lastname: Ellis
authors.forename: Lixia
authors.initials: L
authors.lastname: Jin
authors.forename: Thomas
authors.initials: T
authors.lastname: Steele
authors.forename: Shawn
authors.initials: S
authors.lastname: Stachel
authors.forename: Craig
authors.initials: C
authors.lastname: Coburn
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Simon
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D020890:Neuregulin-1; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human