1. ¹Greater Los Angeles VA Healthcare System, GRECC, Sepulveda, CA, USA
2. ²Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA, USA
3. ³Department of Medicine, University of California, Los Angeles, CA, USA
4. ⁴Department of Neurology, University of California, Los Angeles, CA, USA

Correspondence: Dr GM Cole, Research 151-Greater Los Angeles VA Healthcare System GRECC-11E, UCLA Departments of Medicine and Neurology (SFVP), 16111 Plummer Street, North Hills, CA 91343, USA. Tel: +818 891 7711, ext 9949; Fax: +818 895 5835; E-mail: gmcole@ucla.edu

⁵Current address: Osaka University, Psychiatry, Japan.

Received 10 June 2004; Revised 19 October 2004; Accepted 6 December 2004; Published online 26 January 2005.

Abstract

Epidemiological and basic research suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) should protect against the most common forms of Alzheimer's disease (AD). Ibuprofen reduces amyloid (A) pathology in some transgenic models, but the precise mechanisms remain unclear. Although some reports show select NSAIDs inhibit amyloid production in vitro, the possibility that in vivo suppression of amyloid pathology occurs independent of A production has not been ruled out. We show that ibuprofen reduced A brain levels in rats from exogenously infused A in the absence of altered A production. To determine whether ibuprofen inhibits pro-amyloidogenic factors, APPsw (Tg2576) mice were treated with ibuprofen for 6 months, and expression levels of the A and inflammation-related molecules ₁ antichymotrypsin (ACT), apoE, BACE1, and peroxisome proliferator-activated receptor ) (PPAR) were measured. Among these, ACT, a factor whose overexpression accelerates amyloid pathology, was reduced by ibuprofen both in vivo and in vitro. IL-1, which was reduced in our animals by ibuprofen, induced mouse ACT in vitro. While some NSAIDs may inhibit A42 production, these observations suggest that ibuprofen reduction of A pathology may not be mediated by altered A42 production. We present evidence supporting the hypothesis that ibuprofen-dependent amyloid reduction is mediated by inhibition of an alternate pathway (IL-1 and its downstream target ACT).