INTERLEUKIN-6 AND ALPHA-2-MACROGLOBULIN INDICATE AN ACUTE-PHASE STATE IN ALZHEIMERS-DISEASE CORTICES

Recent studies indicated that the formation of a major constituent of Alzheimer's disease (AD) senile plaques, called beta-A4-peptide, does not result from normal processing of its precursor, amyloid precursor protein (APP). Since proteolytic cleavage of APP inside its beta-A4 sequence was found to be part of APP processing the formation of the beta-A4-peptide seems to be prevented under normal conditions. We considered whether in AD one of the endogenous proteinase inhibitors might interfere with APP processing. After we had recently found that cultured human neuronal cells synthesize the most potent of the known human proteinase inhibitors, alpha-2-macroglobulin (alpha-2M), upon stimulation with the inflammatory mediator interleukin-6 (IL-6) we now investigated whether alpha-2M and IL-6 could be detected in AD brains. Here we report that AD cortical senile plaques display strong alpha-2M and IL-6 immunoreactivity while no such immunoreactivity was found in age-matched control brains. Strong perinuclear alpha-2M immunoreactivity in hippocampal CA1 neurons of Alzheimer's disease brains indicates that neuronal cells are the site of alpha-2M synthesis in AD brains. We did not detect elevated IL-6 or alpha-2M levels in the cerebrospinal fluid of AD patients. Our data indicate that a sequence of immunological events which seem to be restricted to the local cortical environment is part of AD pathology.