Microglial interaction with beta-amyloid: Implications for the pathogenesis of Alzheimer's disease

The etiology of Alzheimer's disease (AD) involves a significant inflammator y component as evidenced by the presence of elevated levels of a diverse ra nge of proinflammatory molecules in the AD brain. These inflammatory molecu les are produced principally by activated microglia, which are found to be clustered within and adjacent to the senile plaque. Moreover, long-term tre atment of patients with non-steroidal anti-inflammatory drugs has been show n to reduce risk and incidence of AD and delay disease progression. The mic roglia respond to beta-amyloid (AP) deposition in the brain through the int eraction of fibrillar forms of amyloid with cell surface receptors, leading to the activation of intracellular signal transduction cascades. The activ ation of multiple independent signaling path ways ultimately leads to the i nduction of proinflammatory gene expression and production of reactive oxyg en and nitrogen species. These microglial inflammatory products act in conc ert to produce neuronal toxicity and death. Therapeutic approaches focused on inhibition of the microglial-mediated local inflammatory response in the AD brain offer new opportunities to intervene in the disease. (C) 2001 Wil ey-Liss, Inc.