A beta Peptides and Calcium Influence Secretion of the Amyloid Protein Precursor From Chick Sympathetic Neurons in Culture

• Published in: Journal of neuroscience research 2000-08, Vol.61 (4), p.449-457
• Main Authors: Mok, Su San, Clippingdale, AB, Beyreuther, K, Masters, CL, Barrow, C J, Small, D H
• Format: Article
• Language: English
• ISSN: 0360-4012
• DOI: 10.1002/1097-4547(20000815)61:4<449::AID-JNR12>3.3.CO;2-E

The major constituent of amyloid plaques in the Alzheimer disease (AD) brain is the amyloid protein (A beta ). A beta has been shown to be neurotoxic to cells, but the exact mechanism of its effects are still not known. Most studies 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 [ super(35)S]methionine and the amounts of radiolabeled APP and A beta quantitated. Several A beta peptides (A beta sub(25-35), [pyroglu super(3)]A beta sub(3-40), and [pyroglu super(11)]A beta sub(11-40)) inhibited secretion of [ super(35)S]APP and increased cell-associated [ super(35)S]APP. There was also a 2-2.5-fold increase in secretion of several other proteins when cells were incubated with A beta sub(25-35). However, the amount of A beta secreted into the medium was decreased. Treatment of cells with the calcium ionophore A23187 caused a 1.5-fold increase in secreted [ super(35)S]APP and a decrease in cell-associated [ super(35)S]APP. Although L-type voltage-dependent calcium channels (VDCC) have been implicated in A beta 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 [ super(35)S]APP secretion into the medium but did not influence the effect of A beta on [ super(35)S]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 function, the accumulation of A beta in the AD brain could decrease secreted APP and thereby indirectly increase A beta toxicity.