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Ibuprofen suppresses interleukin-1β induction of pro-amyloidogenic α1-antichymotrypsin to ameliorate β-amyloid (Aβ) pathology in Alzheimer’s models


Year of Publication:
Contact PI Name:
Greg M. Cole
Contact PI Affiliation:
Greater Los Angeles VA Healthcare System, GRECC, Sepulveda, California, USA
Takashi Morihara, Bruce Teter, Fusheng Yang, Giselle P. Lim, Sally Boudinot, F. Douglas Boudinot, Sally A. Frautschy
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
National Institute of Neurological Disorders and Stroke (NINDS)
Mitsubishi Pharma Research Foundation, Osaka, Japan
Study Goal and Principal Findings:

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 (Aβ) 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 Aβ production has not been ruled out. This study shows that ibuprofen reduced Aβ brain levels in rats from exogenously infused Aβ in the absence of altered Aβ production. To determine whether ibuprofen inhibits proamyloidogenic factors, APPsw (Tg2576) mice were treated with ibuprofen for 6 months, and expression levels of the Aβ and inflammation-related molecules α- antichymotrypsin (ACT), apoE, BACE1, and peroxisome proliferator-activated receptor γ) (PPARγ) were measured. Among these, ACT, a factor whose overexpression accelerates amyloid pathology, was reduced by ibuprofen both in vivo and in vitro. IL-1β, which was reduced in these animals by ibuprofen, induced mouse ACT in vitro. While some NSAIDs may inhibit Aβ42 production, these observations suggest that ibuprofen reduction of Aβ pathology may not be mediated by altered Aβ42 production. This study presents evidence supporting the hypothesis that ibuprofen-dependent amyloid reduction is mediated by inhibition of an alternate pathway (IL-1β and its downstream target ACT).

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
Cyclooxygenase 1 (COX 1)
Therapeutic Target:
Cyclooxygenase 2 (COX 2)

Animal Model

Model Information:
Model Type:
beta Amyloid Peptide Injection
Strain/Genetic Background:
Not Applicable
Model Type:
Strain/Genetic Background:
Not Reported

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
beta Amyloid Deposits
beta Amyloid Load
Brain-beta Amyloid Peptide-Total
Apolipoprotein E (ApoE)
beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1)
Antichymotrypsin (ACT)
Peroxisome Proliferator-Activated Receptor gamma (PPAR gamma)
Cyclooxygenase 2 (COX 2) Activity
Antichymotrypsin (ACT) mRNA
Interleukin 1 beta (IL-1 beta)
Brain-beta Amyloid Deposits