PHYSIOLOGICAL LEVELS OF BETA-AMYLOID INCREASE TYROSINE PHOSPHORYLATION AND CYTOSOLIC CALCIUM

The a beta peptide is a neurotoxic peptide that accumulates in the bra ins of Alzheimer patients, but is also present in body fluids at subna nomolar levels. The potential effects of these low levels of a beta ar e unclear. We now show that one such action is to increase tyrosine ph osphorylation in PC12 cells and olfactory neuroblasts. Application of a beta(25-35) or a beta(1-40) induces a dose-dependent increase in the tyrosine phosphorylation in both whole cells and in vitro. The increa se in tyrosine phosphorylation is both rapid and sensitive, being stim ulated by picomolar doses of a beta and occurring within 1 min of appl ication. Calcium imaging experiments provide further support for the r ole of tyrosine phosphorylation in the action of a beta. While a beta does not alter calcium metabolism under basal conditions, the addition of a beta induces a rapid increase in cytoplasmic calcium in olfactor y neuroblasts that have been treated with the tyrosine phosphatase inh ibitor, sodium orthovanadate or in PC12 cells treated with nerve growt h factor. These responses could be blocked by the tyrosine kinase inhi bitor, herbimycin. These calcium responses displayed an obligate requi rement for the presence of matrix proteins. The identification of a ra pid, sensitive assay for the action of a beta may facilitate investiga tions of its mechanism of action.