title: Elevation of BACE in an Aβ rat model of Alzheimer's disease: exacerbation by chronic stress and prevention by nicotine.
abstract: In Alzheimer's disease (AD), progressive accumulation of β-amyloid (Aβ) peptides impairs nicotinic acetylcholine receptor (nAChR) function by a mechanism that may involve α7 and α4β2-nAChR subtypes. Additionally, the beta-site amyloid precursor protein (APP)-cleaving enzyme (BACE), the rate-limiting enzyme in the pathogenic Aβ production pathway, is expressed at high levels in hippocampal and cortical regions of AD brains. We measured hippocampal area CA1 protein levels of BACE and α7- and α4β2-nAChR subunits using an Aβ rat model of AD (14-d osmotic pump i.c.v. infusion of 300 pmol/d Aβ peptides) in the presence and absence of chronic stress and/or chronic nicotine treatment. There was a significant increase in the levels of BACE in Aβ-infused rats, which were markedly intensified by chronic (4-6 wk) stress, but were normalized in Aβ rats chronically treated with nicotine (1 mg/kg b.i.d.). The levels of the three subunits α7, α4 and β2 were significantly decreased in Aβ rats, but these were also normalized in Aβ rats chronically treated with nicotine. Chronic stress did not further aggravate the reduction of nAChRs in Aβ-infused rats. The increased BACE levels and decreased nAChR levels, which are established hallmarks of AD, provide additional support for the validity of the Aβ i.c.v.-infused rat as a model of AD.
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, USA. kalkadhi@uh.edu
authors.forename: Karim A
authors.initials: KA
authors.lastname: Alkadhi
authors.forename: Karem H
authors.initials: KH
authors.lastname: Alzoubi
authors.forename: Marisa
authors.initials: M
authors.lastname: Srivareerat
authors.forename: Trinh T
authors.initials: TT
authors.lastname: Tran
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology* / Q000209:etiology / Q000517:prevention & control*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D002908:Chronic Disease; D004195:Disease Models, Animal; D008297:Male; D009538:Nicotine / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013315:Stress, Psychological / Q000150:complications / Q000201:enzymology* / Q000517:prevention & control
chemical_list: D016564:Amyloid beta-Protein Precursor; D009538:Nicotine; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509281:Bace1 protein, rat