Inflammatory mechanisms in Alzheimer's disease: Inhibition of beta-amyloid-stimulated proinflammatory responses and neurotoxicity by PPAR gamma agonists
Ck. Combs et al., Inflammatory mechanisms in Alzheimer's disease: Inhibition of beta-amyloid-stimulated proinflammatory responses and neurotoxicity by PPAR gamma agonists, J NEUROSC, 20(2), 2000, pp. 558-567
Alzheimer's disease (AD) is characterized by the extracellular deposition o
f beta-amyloid fibrils within the brain and the subsequent association and
phenotypic activation of microglial cells associated with the amyloid plaqu
e. The activated microglia mount a complex local proinflammatory response w
ith 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 perox
isome proliferator-activated receptor gamma (PPAR gamma). PPAR gamma is a D
NA-binding transcription factor whose transcriptional regulatory actions ar
e activated after agonist binding. We report that NSAIDs, drugs of the thia
zolidinedione class, and the natural ligand prostaglandin J2 act as agonist
s for PPAR gamma and inhibit the beta-amyloid-stimulated secretion of proin
flammatory products by microglia and monocytes responsible for neurotoxicit
y and astrocyte activation. The activation of PPAR gamma also arrested the
differentiation of monocytes into activated macrophages. PPAR gamma agonist
s were shown to inhibit the beta-amyloid-stimulated expression of the cytok
ine genes interleukin-6 and tumor necrosis factor alpha. Furthermore, PPAR
gamma agonists inhibited the expression of cyclooxygenase-2. These data pro
vide direct evidence that PPAR gamma plays a critical role in regulating th
e inflammatory responses of microglia and monocytes to beta-amyloid. We arg
ue that the efficacy of NSAIDs in the treatment of AD may be a consequence
of their actions on PPAR gamma rather than on their canonical targets the c
yclooxygenases. Importantly, the efficacy of these agents in inhibiting a b
road range of inflammatory responses suggests PPAR gamma agonists may provi
de a novel therapeutic approach to AD.