INTERACTION OF ALZHEIMER BETA-AMYLOID PEPTIDE WITH THE HUMAN MONOCYTIC CELL-LINE THP-1 RESULTS IN A PROTEIN-KINASE C-DEPENDENT SECRETION OFTUMOR-NECROSIS-FACTOR-ALPHA

Immunological mechanisms, including stimulation of brain microglia and elevation of various inflammatory cytokines, have been implicated in the pathogenesis of Alzheimer's disease, where accumulation of beta-am yloid peptide (A beta) is one of its main pathological features. In th is study we investigated the interaction of human monocyte-like cells with synthetic beta-amyloid peptide A beta(1-40) and its subfragment A P(25-35). THP-1 cells (a transformed human monocyte cell line) were us ed with or without prior differentiation by phorbol myristate acetate (PMA), and cell activation was assessed by the secretion of tumor necr osis factor-alpha (TNF-alpha). First, it was shown that THP-1 cells co uld be induced to secrete significant amounts of TNF-alpha by interleu kin-l, lipopolysaccharide, interferon-gamma (IFN-gamma) and PMA alone or in combination with each other. Next it was shown that A beta(1-40) could also induce secretion of TNF-alpha by THP-1 cells, but the effe ct was diminished when this peptide was applied in combination with IF N-gamma. The A beta subfragment A beta(25-35) was ineffective in induc ing TNF-alpha production. The cellular action of A beta(1-40) appears to involve protein kinase C since pretreatment of THP-I cells by PMA o r the protein kinase C inhibitor H-7 diminished the cellular response to A beta(1-40). Identification of the pathway by which extracellular A beta activates the intracellular PKC-dependent secretion of TNF-alph a may help in developing new therapeutic strategies for Alzheimer's di sease.