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

Abstract

The etiology of Alzheimer's disease (AD) involves a significant inflammatory component as evidenced by the presence of elevated levels of a diverse range of proinflammatory molecules in the AD brain. These inflammatory molecules are produced principally by activated microglia, which are found to be clustered within and adjacent to the senile plaque. Moreover, long-term treatment of patients with non-steroidal anti-inflammatory drugs has been shown to reduce risk and incidence of AD and delay disease progression. The microglia respond to beta-amyloid (Abeta) deposition in the brain through the interaction of fibrillar forms of amyloid with cell surface receptors, leading to the activation of intracellular signal transduction cascades. The activation of multiple independent signaling pathways ultimately leads to the induction of proinflammatory gene expression and production of reactive oxygen and nitrogen species. These microglial inflammatory products act in concert 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.