GLIAL-NEURONAL INTERACTIONS IN ALZHEIMERS-DISEASE - THE POTENTIAL ROLE OF A CYTOKINE CYCLE IN DISEASE PROGRESSION

The role of glial inflammatory processes in Alzheimer's disease has be en highlighted by recent epidemiological work establishing head trauma as an important risk factor, and the use of anti-inflammatory agents as an important ameliorating factor, in this disease, This review adva nces the hypothesis that chronic activation of glial inflammatory proc esses, arising from genetic or environmental insults to neurons and ac companied by chronic elaboration of neuroactive glia-derived cytokines and other proteins, sets in motion a cytokine cycle of cellular and m olecular events with neurodegenerative consequences, In this cycle, in terleukin-1 is a key initiating and coordinating agent. Interleukin-1 promotes neuronal synthesis and processing of the beta-amyloid precurs or protein, thus favoring continuing deposition of beta-amyloid, and a ctivates astrocytes and promotes astrocytic synthesis and release of a number of inflammatory and neuroactive molecules, One of these, S100 beta, is a neurite growth-promoting cytokine that stresses neurons thr ough its trophic actions and fosters neuronal cell dysfunction and dea th by raising intraneuronal free calcium concentrations. Neuronal inju ry arising from these cytokine-induced neuronal insults can activate m icroglia with further overexpression of interleukin-1, thus producing feedback amplification and self-propagation of this cytokine cycle, Ad ditional feedback amplification is provided through other elements of the cycle, Chronic propagation of this cytokine cycle represents a pos sible mechanism for progression of neurodegenerative changes culminati ng in Alzheimer's disease.