THE PARTICIPATION OF INTERLEUKIN-6, A STRESS-INDUCIBLE CYTOKINE, IN THE PATHOGENESIS OF ALZHEIMERS-DISEASE

A loss of synapses in the cortices of demented persons appears to be t he primary correlate of Alzheimer's disease (AD). However, it is still unclear how synaptic pathology is connected to other pathological fin dings such as neurofibrillary and neuritic degeneration or inflammator y markers in AD. Interleukin-6 (IL-6) immunoreactivity has previously been detected in plaques in the brains of AD patients. Ln addition, el evated IL-6 concentrations have been measured biochemically in the bra ins of AD patients. Since transgenic mice bearing additional copies of the IL-6 gene under the control of a brain-specific promoter develop a marked cortical pathology including severe alterations of the dendri tic arborization of cortical neurons, an IL-6 related inflammatory eve nt could well be connected to the synaptic pathology in AD. In this st udy, we investigated whether IL-6 immunoreactivity in plaques could al ready be found prior to the onset of neuritic changes, or whether the presence of this cytokine is restricted to the later stages of plaque formation. While diffuse plaques represent an early stage of plaque fo rmation, primitive and classic plaques (displaying neuritic pathology) are thought to reflect later stages of plaque pathology. Using a silv er-staining method, we classified plaque stages in serial sections of paraffin-embedded cortices of clinically diagnosed and histopathologic ally confirmed AD patients and of control persons with no clinical his tory of dementia. Adjacent sections were stained with an antibody dire cted against IL-6. IL-6 was detectable in a significant proportion of plaques, but only in the brains of demented patients. In the AD cases, IL-6 was found in diffuse plaques in a significantly higher ratio as would have been expected from a random distribution of IL-6 among all plaque types. This observation suggests that IL-6 expression may prece de neuritic changes and that in AD an immunological mechanism may be i nvolved both in the transformation from diffuse to primitive plaques a nd in the development of dementia. The reasons for the increased expre ssion of IL-6 in the brains of AD patients are still unknown. Basal IL -6 levels were found to be slightly elevated along normal aging. Based on several studies indicating that IL-6 expression is inducible also by psychological stress, one could speculate whether long-lasting stre ssful experiences may contribute to the pathological process underlyin g Alzheimer's disease.