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The Journal of Neuroscience, January 15, 2000, 20(2):558-567
Inflammatory Mechanisms in Alzheimer's Disease: Inhibition of
 -Amyloid-Stimulated Proinflammatory Responses and Neurotoxicity by
PPAR Agonists
Colin K.
Combs,
Derrick E.
Johnson,
J. Colleen
Karlo,
Steven B.
Cannady, and
Gary E.
Landreth
Alzheimer Research Laboratory, Departments of Neurosciences and
Neurology, Case Western Reserve University School of Medicine,
Cleveland, Ohio 44106
Alzheimer's disease (AD) is characterized by the extracellular
deposition of  -amyloid fibrils within the brain and the subsequent association and phenotypic activation of microglial cells associated with the amyloid plaque. The activated microglia mount a complex local
proinflammatory response with the secretion of a diverse range of
inflammatory products. Nonsteroidal anti-inflammatory drugs (NSAIDs)
are efficacious in reducing the incidence and risk of AD and
significantly delaying disease progression. A recently appreciated
target of NSAIDs is the ligand-activated nuclear receptor peroxisome
proliferator-activated receptor  (PPAR). PPAR is a DNA-binding
transcription factor whose transcriptional regulatory actions are
activated after agonist binding. We report that NSAIDs, drugs of the
thiazolidinedione class, and the natural ligand prostaglandin J2
act as agonists for PPAR and inhibit the -amyloid-stimulated secretion of proinflammatory products by microglia and monocytes responsible for neurotoxicity and astrocyte activation. The activation of PPAR also arrested the differentiation of monocytes into
activated macrophages. PPAR agonists were shown to inhibit the
-amyloid-stimulated expression of the cytokine genes
interleukin-6 and tumor necrosis factor  . Furthermore,
PPAR agonists inhibited the expression of cyclooxygenase-2. These
data provide direct evidence that PPAR plays a critical role in
regulating the inflammatory responses of microglia and monocytes to
-amyloid. We argue that the efficacy of NSAIDs in the treatment of
AD may be a consequence of their actions on PPAR rather than on
their canonical targets the cyclooxygenases. Importantly, the efficacy
of these agents in inhibiting a broad range of inflammatory responses
suggests PPAR agonists may provide a novel therapeutic approach to AD.
Key words:
Alzheimer's disease; -amyloid; microglia; THP-1
monocytes; signal transduction; tyrosine kinase; inflammation; neurotoxicity; PPAR; cyclooxygenase; TNF; IL-6; NSAIDs; cytokines; COX-2
Copyright © 2000 Society for Neuroscience 0270-6474/00/202558-10$05.00/0
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