Glial cell reactions in neurodegenerative diseases: pathophysiology and therapeutic interventions

A variety of proteins known to be involved in inflammatory processes are associated with lesions in chronic neurodegenerative disorders such as Alzheimer disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). This is particularly true of AD, in which inflammatory reactions are believed to be important contributors to the neuronal loss. Inflammatory proteins associated with AD include complement proteins, complement inhibitors, acute-phase reactants, inflammatory cytokines, proteases, and protease inhibitors. Studies of cultured human astrocytes and microglia obtained from postmortem brain have established that almost all of these proteins are produced by one or the other of these two cell types. Human neurons also produce many inflammatory proteins and their inhibitors, creating complex interactions. Accumulations of amyloid, extracellular tangles, or Lewy bodies apparently act as irritants, causing the activation of complement, the initiation of reactive changes in microglia, and the release of potentially neurotoxic products such as the membrane attack complex, oxygen free radicals, and excess glutamate. A number of epidemiologic studies indicate that populations taking anti-inflammatory drugs have a sharply reduced prevalence of AD. One small clinical trial with indomethacin showed arrest of the disease over a 6-month period. Therapeutic intervention in key inflammatory processes holds great promise for the amelioration of AD and possibly other neurodegenerative disorders.