Inflammatory mechanisms in Alzheimer's disease: Inhibition of beta-amyloid-stimulated proinflammatory responses and neurotoxicity by PPAR gamma agonists

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.