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The Journal of Neuroscience, August 20, 2003, 23(20):7504-7509
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Anti-Inflammatory Drug Therapy Alters  -Amyloid Processing and Deposition in an Animal Model of Alzheimer's Disease
Qiao Yan,1
Jianhua Zhang,1
Hantao Liu,1
Safura Babu-Khan,1
Robert Vassar,1
Anja Leona Biere,1
Martin Citron,1 and
Gary Landreth2
1Department of Neuroscience, Amgen Inc., Thousand
Oaks, California 91320, and 2Alzheimer Research
Laboratory, Department of Neurosciences, Case Western Reserve University,
Cleveland, Ohio 44106
Alzheimer's disease (AD) is characterized by a microglial-mediated
inflammatory response elicited by extensive amyloid deposition in the brain.
Nonsteroidal anti-inflammatory drug (NSAID) treatment reduces AD risk, slows
disease progression, and reduces microglial activation; however, the basis of
these effects is unknown. We report that treatment of 11-month-old Tg2576 mice
overexpressing human amyloid precursor protein (APP) with the NSAID ibuprofen
for 16 weeks resulted in the dramatic and selective reduction of SDS-soluble
 -amyloid (A)42, whereas it had smaller effects on
SDS-soluble A40 levels. Ibuprofen treatment resulted in 60%
reduction of amyloid plaque load in the cortex of these animals. In
vitro studies using APP-expressing 293 cells showed that ibuprofen
directly affected APP processing, specifically reducing the production of
A42. Ibuprofen treatment resulted in a significant reduction
in microglial activation in the Tg2576 mice, as measured by CD45 and CD11b
expression. NSAIDs activate the nuclear hormone receptor peroxisome
proliferator-activated receptor  (PPAR); however, a potent
agonist of this receptor, pioglitazone, only modestly reduced SDS-soluble
A levels and did not affect amyloid plaque burden or microglia
activation, indicating that PPAR activation is not involved in the
A lowering effect of NSAIDs. These data show that chronic NSAID
treatment can reduce brain A levels, amyloid plaque burden, and
microglial activation in an animal model of Alzheimer's disease.
Key words: Alzheimer's disease; NSAIDs; -amyloid; PPAR; inflammation; microglia
Received Jan. 21, 2003;
revised May. 29, 2003;
accepted Jun. 3, 2003.
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Another Noteworthy Paper This Week
Sci. Aging Knowl. Environ.,
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[Full Text]
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