1. ^*Institute of General Pathology, University of Verona, 37134 Verona, Italy
2. ^†Institute of Neurology, University of Milano, 20122 Milano, Italy
3. ^‡Wistar Institute, Philadelphia, Pennsylvania 19104, USA
4. ^§Institute of General Pathology, University of Ferrara, 44100 Ferrara, Italy

Abstract

ALZHEIMER'S disease is the most common cause of progressive intellectual failure¹. The lesions that develop, called senile plaques, are extracellular deposits principally composed of insoluble aggregates of -amyloid protein (A), infiltrated by reactive microglia and astrocytes^2,3. Although A, and a portion of it, the fragment 25–35 (A(25–35)), have been shown to exert a direct toxic effect on neurons^4–6, the role of microglia in such neuronal injury remains unclear⁷. Here we report a synergistic effect between A and interferon- (IFN-) in triggering the production of reactive nitrogen intermediates and tumour-necrosis factor- (TNF-) from microglia. Furthermore, using co-culture experiments, we show that activation of microglia with IFN- and A leads to neuronal cell injury in vitro. These findings suggest that A and IFN- activate microglia to produce reactive nitrogen intermediates and TNF-, and this may have a role in the pathogenesis of neuronal degeneration observed in ageing and Alzheimer's disease.