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Modulation of nuclear factor-κb activity by indomethacin influences Aβ levels but not Aβ precursor protein metabolism in a model of Alzheimer’s disease


Year of Publication:
Contact PI Name:
Domenico Pratico
Contact PI Affiliation:
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
Syaun Sung, Hengxuan Yang, Kunihiro Uryu, Edward B. Lee, Lei Zhao, Diana Shineman, John Q. Trojanowski, Virginia M-Y. Lee
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
Alzheimer's Association
Coins for Alzheimer’s Research Trust
Study Goal and Principal Findings:

Epidemiological studies show that some nonsteroidal anti-inflammatory drugs, nonspecific inhibitors of the cyclooxygenase enzyme, reduce the incidence of Alzheimer’s disease (AD). They determined the impact of two nonsteroidal anti-inflammatory drugs on Aβ levels, deposition, and metabolism in a mouse model (the Tg2576) of AD-like amyloidosis. To this end, mice were treated with indomethacin and nimesulide continuously from 8 months of age until they were 15 months old. At the end of the study, indomethacin significantly reduced Aβ1-40 and Aβ1-42 levels in both cortex and hippocampus. This decrease was coincidental with a significant reduction of the nuclear factor (NF)-κB activity. By contrast, nimesulide had no effect on both Aβ peptides and NF-κB. Consistently, mice receiving indomethacin, but no nimesulide, showed a significant reduction in the amyloid burden compared with placebo. Neither drug had an effect on plasma levels of Aβ peptides or the Aβ precursor protein metabolism. In vitro studies confirmed that genetic absence of this factor reduces the anti amyloidogenic effect of indomethacin. These findings indicate that chronic administration of indomethacin by blocking the activation of the NF-κB significantly reduces the amyloid pathology in Tg2576 mice, and provide insights into the mechanisms by which this drug could slow progression of AD.

Therapeutic Agent

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

Animal Model

Model Information:
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
Prostaglandin E2 (PGE2)
Thromboxane B2 (TxB2)
Soluble Amyloid Precursor Protein beta (sAPP beta)
Brain-beta Amyloid Oligomers
Glial Fibrillary Acidic Protein (GFAP)
Tumor Growth Factor beta (TGF beta)
Cyclooxygenase 1 (COX 1) activity
Cyclooxygenase 2 (COX 2) Activity
Cyclooxygenase 1 (COX 1)
Cyclooxygenase 2 (COX 2)
Brain-Buffer Soluble beta Amyloid Peptide 40
Brain-Buffer Soluble beta Amyloid Peptide 42
Brain-Buffer Insoluble beta Amyloid Peptide 40
Brain-Buffer Insoluble beta Amyloid Peptide 42
8,12-iso-isoprostane F2 alpha VI
Urine-2,3-dinor-Thromboxane B2
Urine-2,3-dinor-6-keto-PGF1 alpha
Brain-beta Amyloid Deposits
Plasma-beta Amyloid Peptides
Drug Concentration-Plasma
Target Engagement (Inhibition Cyclooxygenase 1/2)
Body Weight
Toxicity-Gastrointestinal (GI)
General Health