Ibuprofen Suppresses Interleukin-1β Induction of Pro-Amyloidogenic α1-Antichymotrypsin to Ameliorate β-Amyloid (Aβ) Pathology in Alzheimer's Models

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 (Ab) 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 Ab production has not been ruled out. We show that ibuprofen reduced Ab brain levels in rats from exogenously infused Ab in the absence of altered Ab production. To determine whether ibuprofen inhibits proamyloidogenic factors, APPsw (Tg2576) mice were treated with ibuprofen for 6 months, and expression levels of the Ab and inflammation-related molecules a 1 antichymotrypsin (ACT), apoE, BACE1, and peroxisome proliferator-activated receptor g) (PPARg) were measured. Among these, ACT, a factor whose overexpression accelerates amyloid pathology, was reduced by ibuprofen both in vivo and in vitro. IL-1b, which was reduced in our animals by ibuprofen, induced mouse ACT in vitro. While some NSAIDs may inhibit Ab42 production, these observations suggest that ibuprofen reduction of Ab pathology may not be mediated by altered Ab42 production. We present evidence supporting the hypothesis that ibuprofen-dependent amyloid reduction is mediated by inhibition of an alternate pathway (IL-1b and its downstream target ACT).

Prevention of Alzheimer's disease: Omega-3 fatty acid and phenolic anti-oxidant interventions

“…With low dosing designed to model apparently protective chronic NSAID consumption in populations with reduced AD risk, ibuprofen suppressed amyloid accumulation in APPsw transgenic mice [16] but reduced a surprisingly limited subset of inflammatory markers, notably IL-1␤ and downstream murine ACT mRNA, but not iNOS, macrosialin or CD11c mRNA [19]. Further, some NSAIDs including ibuprofen (but not naproxen and COX-2 inhibitors) selectively lowered A␤1-42 production without inhibiting A␤1-40 or NOTCH in vitro or in vivo [8,32].…”

Microglial NLRP3 Activity in Alzheimer's Disease

“…In another study, the treatment with mefenamic acid, another NSAID drug, reduced neural cell toxicity and protected rats from memory deficits [53]. Furthermore, ibuprofen specifically reduced pro-amyloidogenic α1 antichymotrypsin in vitro and in vivo by suppressing IL-1β [54]. These findings indicate that NSAID targeting NLRP3 pathway may be promising drug candidates for the treatment of patients with AD.…”

Alzheimer's Factors in Ischemic Brain Injury

“…From these observations considerable studies were undertaken to investigate the influence of anti-inflammation treatment in ischemic and amyloid brain diseases. These studies include nonsteroidal antiinflammatory therapy (Morihara et al, 2005), cannabinoids (Ramirez et al, 2005) and peroxisome proliferator-activated receptor-agonists (Sastre et al, 2003;Echeverria et al, 2005;Heneka et al, 2005;Sastre et al, 2006). Current results from transgenic model of amyloid pathology was presented data that therapy against -secretase decreases reaction of neuroinflammation in brain (Rakover et al, 2007).…”