GLIAL CYTOKINES IN ALZHEIMERS-DISEASE - REVIEW AND PATHOGENIC IMPLICATIONS

The roles of activated glia and of glial cytokines in the pathogenesis of Alzheimer's disease are reviewed. Interleukin-1 (IL-1), a microgli a-derived acute phase cytokine, activates astrocytes and induces expre ssion of the astrocyte-derived cytokine, S100 beta, which stimulates n eurite growth (and thus has been implicated in neuritic plaque formati on) and increases intracellular free calcium levels. Interleukin-1 als o upregulates expression and processing of beta-amyloid precursor prot eins (beta-APPs) (thus favoring beta-amyloid deposition) and induces e xpression of alpha(1)-antichymotrypsin, thromboplastin, the complement protein C3, and apolipoprotein E, all of which are present in neuriti c plaques. These cytokines, and the molecular and cellular events that they engender, form a complex of interactions that may be capable of self-propagation, leading to chronic overexpression of glial cytokines with neurodegenerative consequences. Self-propagation maybe facilitat ed by means of several reinforcing feedback loops. beta-Amyloid, for i nstance, directly activates microglia, thus inducing further IL-1 prod uction, and activates the complement system, which also leads to micro glial activation with IL-1 expression. Self-propagation also could res ult when S100 beta-induced increases in intraneuronal free calcium lev els lead to neuronal injury and death with consequent microglial activ ation. Such chronic, self-propagating, cytokine-mediated molecular and cellular reactions would explain the progressive neurodegeneration an d dementia of Alzheimer's disease. HUM PATHOL 26:816-823. Copyright (C ) 1995 by W.B. Saunders Company.