A beta peptides and calcium influence secretion of the amyloid protein precursor from chick sympathetic neurons in culture

The major constituent of amyloid plaques in the Alzheimer disease (AD) brai n is the amyloid protein (A beta). A beta has been shown to be neurotoxic t o cells, but the exact mechanism of its effects are still not known. Most s tudies have focussed on A beta neurotoxicity, but little is known about the effect of A beta peptides on cellular protein metabolism and secretion. To examine the effect of A beta peptides on APP secretion, chick sympathetic neurons were metabolically labeled with [S-35]methionine and the amounts of radiolabeled APP and A beta quantitated. Several A beta peptides (A beta(2 5-35), [pyroglu(3)]A beta(3-40), and [pyroglu(11)]A beta(11-40)) inhibited secretion of [S-35]APP and increased cell-associated [S-35]APP. There was a lso a 2-2.5-fold increase in secretion of several other proteins when cells were incubated with A beta(25-35). However, the amount of A beta secreted into the medium was decreased. Treatment of cells with the calcium ionophor e A23187 caused a 1.5-fold increase in secreted [S-35]APP and a decrease in cell-associated [S-35]APP. Although L-type voltage-dependent calcium chann els (VDCC) have been implicated in A beta toxicity, the effect of L-type VD CC on APP secretion has not previously been examined. The L-type VDCC antag onists nifedipine and diltiazem both increased [S-35]APP secretion into the medium but did not influence the effect of A beta on [S-35]APP secretion. These studies suggest that A beta interferes with the secretory pathway of APP. Insofar as secreted APP has been proposed to have a neuroprotective fu nction, the accumulation of A beta in the AD brain could decrease secreted APP and thereby indirectly increase A beta toxicity. (C) 2000 Wiley-Liss, I nc.