Glial cell reactions in neurodegenerative diseases: Pathophysiology and therapeutic interventions

A variety of proteins known to be involved in inflammatory processes are as sociated with lesions in chronic neurodegenerative disorders such as Alzhei mer disease (AD), Parkinson's disease (PD), and amyotrophic lateral scleros is (ALS). This is particularly true of AD, in which inflammatory reactions are believed to be important contributors to the neuronal loss. Inflammator y proteins associated with AD include complement proteins, complement inhib itors, acute-phase reactants, inflammatory cytokines, proteases, and protea se inhibitors. Studies of cultured human astrocytes and microglia obtained from postmortem brain have established that almost all of these proteins ar e produced by one or the other of these two cell types. Human neurons also produce many inflammatory proteins and their inhibitors, creating complex i nteractions. Accumulations of amyloid, extracellular tangles, or Lewy bodie s apparently act as irritants, causing the activation of complement, the in itiation of reactive changes in microglia, and the release of potentially n eurotoxic products such as the membrane attack complex, oxygen free radical s, and excess glutamate. A number of epidemiologic studies indicate that po pulations taking anti-inflammatory drugs have a sharply reduced prevalence of AD. One small clinical trial with indomethacin showed arrest of the dise ase over a 6-month period. Therapeutic intervention in key inflammatory pro cesses holds great promise for the amelioration of AD and possibly other ne urodegenerative disorders.