Elevation of BACE in an Aβ rat model of Alzheimer's disease: exacerbation by chronic stress and prevention by nicotine

In Alzheimer's disease (AD), progressive accumulation of beta-amyloid (A beta) peptides impairs nicotinic acetylcholine receptor (nAChR) function by a mechanism that may involve alpha(7) and alpha(4)beta(2)-nAChR subtypes. Additionally, the beta-site amyloid precursor protein (APP)-cleaving enzyme (BACE), the rate-limiting enzyme in the pathogenic A beta 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 alpha(7)- and alpha(4)beta(2)-nAChR subunits using an A beta rat model of AD (14-d osmotic pump i.c.v. infusion of 300 pmol/d A beta 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 A beta-infused rats, which were markedly intensified by chronic (4-6 wk) stress, but were normalized in A beta rats chronically treated with nicotine (1 mg/kg b.i.d.). The levels of the three subunits alpha(7), alpha(4) and beta(2) were significantly decreased in A beta rats, but these were also normalized in A beta rats chronically treated with nicotine. Chronic stress did not further aggravate the reduction of nAChRs in A beta-infused rats. The increased BACE levels and decreased nAChR levels, which are established hallmarks of AD, provide additional support for the validity of the A beta i.c.v.-infused rat as a model of AD.