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

Abstract

The major constituent of amyloid plaques in the Alzheimer disease (AD) brain is the amyloid protein (Aβ). Aβ has been shown to be neurotoxic to cells, but the exact mechanism of its effects are still not known. Most studies have focussed on Aβ neurotoxicity, but little is known about the effect of Aβ peptides on cellular protein metabolism and secretion. To examine the effect of Aβ peptides on APP secretion, chick sympathetic neurons were metabolically labeled with [35S]methionine and the amounts of radiolabeled APP and Aβ quantitated. Several Aβ peptides (Aβ25–35, [pyroglu3]Aβ3–40, and [pyroglu11]Aβ11–40) inhibited secretion of [35S]APP and increased cell-associated [35S]APP. There was also a 2–2.5-fold increase in secretion of several other proteins when cells were incubated with Aβ25–35. However, the amount of Aβ secreted into the medium was decreased. Treatment of cells with the calcium ionophore A23187 caused a 1.5-fold increase in secreted [35S]APP and a decrease in cell-associated [35S]APP. Although L-type voltage-dependent calcium channels (VDCC) have been implicated in Aβ toxicity, the effect of L-type VDCC on APP secretion has not previously been examined. The L-type VDCC antagonists nifedipine and diltiazem both increased [35S]APP secretion into the medium but did not influence the effect of Aβ on [35S]APP secretion. These studies suggest that Aβ interferes with the secretory pathway of APP. Insofar as secreted APP has been proposed to have a neuroprotective function, the accumulation of Aβ in the AD brain could decrease secreted APP and thereby indirectly increase Aβ toxicity. J. Neurosci. Res. 61:449–457, 2000. © 2000 Wiley-Liss, Inc.