Glial-Neuronal Interactions in Alzheimer Disease

Abstract

Activated microglia, overexpressing interleukin-1 (IL-1), and activated astrocytes, overexpressing S100beta, have been implicated in the formation and evolution of tau2-immunoreactive (tau2+) neuritic plaques in Alzheimer disease. In this study, we assessed the role of IL-1alpha+ microglia and S100beta+ astrocytes in the pathogenesis of another cardinal histopathological feature of Alzheimer disease: tau2+ neurofibrillary tangles. Four distinct stages of neurofibrillary tangle formation were identified: neurons with granular perikaryal tau2 immunoreactivity (stage 0); fibrillar neuronal inclusions (stage 1); dense, neuronal soma-filling inclusions (stage 2); and acellular, fibrillar deposits (stage 3, "ghost tangles"). The numbers of tangles in randomly selected fields of parahippocampal cortex from 11 Alzheimer patients correlated with both the numbers of IL-1alpha+ microglia and the numbers of S100beta+ astrocytes in these fields (r = 0.72, p < 0.02; r = 0.73, p = 0.01, respectively). There were progressive increases in frequency of association between tangle stages and both IL-1alpha+ microglia and S100beta+ astrocytes: 48, 56, 67, and 92% of stage 0-3 tangles, respectively, had associated IL-1alpha+ microglia; and 21, 37, 55, and 91% of stage 0-3 tangles had associated S100beta+ astrocytes. This progressive association of activated IL-1alpha+ microglia and activated S100beta+ astrocytes with tau2+ tangle stages suggests a role for glial-neuronal interactions in the degeneration of tangle-bearing neurons in Alzheimer disease.