Neuroinflammatory Mechanisms in Alzheimer Disease
Kinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Wesbrook Mall, Vancouver, B.C., V6T 1Z3, Canada
It is now established through work in many laboratories that Alzheimer disease (AD) lesions are characterized by the presence of a broad spectrum of inflammatory molecules. They include complement proteins and their regulators, inflammatory cytokines, acute phase reactants and numerous proteases and protease inhibitors. Neurons, astrocytes and microglia all participate in their production, which is generally upregulated in AD. A chronic neuroinflammatory state exists. Several of these inflammatory products are toxic to neurons and may be contributing in a major way to the progressive neuronal loss of AD. Direct support for this conclusion comes from epidemiological studies indicating that patients taking antiinflammatory drugs have a substantially reduced risk of contracting AD. Nonsteroidal antiinflammatory drugs (NSAIDs) confer greater protection than other antiinflammatory classes. Postmortem studies
show that NSAID users have fewer activated microglia associated with their amyloid deposits than do those not using NSAIDs. Clearly intervening in the AD neuroinflammatory process is a promising approach to therapy. Inflammatory mediators act synergistically, offering many pharmacological targets. The most powerful system, and probably the most dangerous to host tissue, is complement. The complement system can be activated in vitro by several molecules associated with AD lesions, the most abundant of which is b-amyloid protein (Ab). Activated complement fragments richly decorate AD lesions. In particular, the membrane attack complex (MAC) is observed attached to damaged neurites. In vitro, C1q promotes the fibrillar aggregation of b-amyloid. A sequence of events can thus be hypothesized, where lesion associated molecules, such as Ab, activate complement. The activated components promote fibrillar amyloid formation and, through the MAC, directly attack neurites. This leads to a further release of complement-activating molecules, thus sustaining an autotoxic loop which could account for the abrupt clinical decline in AD. The complement system may be a prime target for new drug development.