Microglia mediate an immune response; to beta-amyloid peptides: Implications for the pathogenesis of Alzheimer's disease

Alzheimer's disease (AD) is the most common form of age-related dementia affecting half of the population over age 85. AD is characterized by the appearance of neuropil threads composed of structurally abnormal neurites, neurons containing paired helical filaments of tau protein and extracellular deposits of β-amyloid (Aβ) peptide, a protein having neurotoxic and glial immune activating potential. The observation of activated microglia and astrocytes closely associated with neuritic plaques suggests these cells may contribute to disease progression by initiating and propagating inflammation. The purpose of this dissertation is to determine potential contributions of glial-derived inflammatory mediators to the pathogenesis of AD. Using in vitro and in vivo model systems, I demonstrate that microglia and astrocytes produce the cytokines IL-1α, IL-1β, IL-6 and TNF-α and the chemokine MCP-1 in response to Aβ peptide fragments found in diffuse amyloid deposits and neuritic plaques. These findings provide direct evidence of a possible role for pro-inflammatory cytokines in the evolution of neuritic plaques. The Aβ-induced immune response profile was characterized and found to be similar to the bacterial endotoxin lipopolysaccharide suggesting potential common regulatory mechanisms in the immune response elicited by these two distinct proteins. Furthermore, the ability of the endogenous anti-inflammatory interleukins IL-4, IL-10 and IL-13 to regulate Aβ-induced cytokines and chemokines was characterized. While anti-inflammatory interleukins were expressed in the normal human central nervous system (CNS), the expression level of these inflammatory regulators was diminished in older individuals with AD suggesting an “immune disorder” aspect to the disease. In vitro observations were extended to include examination of a novel animal model of Aβ-induced neuroinflammation. This animal model was used to validate the ability of IL-10 and anti-inflammatory glucocorticoids to inhibit Aβ-induced cytokines and chemokines in the CNS, suggesting these agents can interfere with Aβ-induced immune activation. In summary, I demonstrate microglia are capable of producing the immunopathology associated with the evolution of neuritic plaques and that endogenous CNS factors are capable of modifying the glial response to amyloid peptides. This work provides unique insights into the pathogenesis of AD and offers novel avenues for exploration in the search for effective therapies.