AMYLOID-BETA PEPTIDE POTENTIATES CYTOKINE SECRETION BY INTERLEUKIN-1-BETA-ACTIVATED HUMAN ASTROCYTOMA-CELLS

Neurodegenerative processes in Alzheimer disease (AD) are thought to b e driven in part by the deposition of amyloid beta (A beta), a 39- to 43-amino acid peptide product resulting from an alternative cleavage o f amyloid precursor protein. Recent descriptions of in vitro neurotoxi c effects of A beta support this hypothesis and suggest toxicity might be mediated by A beta-induced neuronal calcium disregulation. In addi tion, it has been reported that ''aging'' A beta results in increased toxic potency due to peptide aggregation and formation of a beta-sheet secondary structure. In addition, A beta might also promote neuropath ology indirectly by activating immune/inflammatory pathways in affecte d areas of the brain (e.g., cortex and hippocampus). Here we report th at A beta can modulate cytokine secretion [interleukins 6 and 8 (IL-6 and IL-8)] from human astrocytoma cells (U-373 MG). Freshly prepared a nd aged AP modestly stimulated IL-6 and IL-8 secretion from U-373 MG c ells, However, in the presence of interleukin-1 beta (IL-1 beta), aged , but not fresh, A beta markedly potentiated (3- to 8-fold) cytokine r elease. In contrast, aged A beta did not potentiate substance P (NK-1) - or histamine (H-1)-stimulated cytokine production. Further studies s howed that IL-1 beta-induced cytokine release was potentiated by A bet a-(25-35), while A beta-(1-16) was inactive. Calcium disregulation may be responsible for the effects of A beta on cytokine production, sinc e the calcium ionophore A23187 similarly potentiated IL-1 beta-induced cytokine secretion and EGTA treatment blocked either A beta or A23187 activity. Thus, chronic neurodegeneration in AD-affected brain region s may be mediated in part by the ability of A beta to exacerbate infla mmatory pathways in a conformation-dependent manner.