Amyloid- [beta] peptide induces temporal membrane biphasic changes in astrocytes through cytosolic phospholipase A₂

Abstract

Oligomeric amyloid-[beta] peptide (A[beta]) is known to induce cytotoxic effects and damage cell functions in Alzheimer's disease. However, mechanisms underlying the effects of A[beta] on cell membranes have yet to be fully elucidated. In this study, A[beta] 1-42 (A[beta][subscript 42]) was shown to cause a temporal biphasic change in membranes of astrocytic DITNC cells using fluorescence microscopy of Laurdan. A[beta][subscript 42] made astrocyte cell membranes become more molecularly-disordered after 30 minutes to 1 hour, transitioning to more molecularly-ordered after 3 hours. However, A[beta][subscript 42] caused artificial vesicle membranes made of rat whole brain lipid extract to become more disordered only. The trend for more molecularly-ordered membranes in astrocytes was abrogated by either an NADPH oxidase inhibitor, apocynin, or an inhibitor of cytosolic phospholipase A[subscript 2] (cPLA[subscript 2]), but not by an inhibitor of calcium-independent PLA2 (iPLA[subscript 2]). Apocynin also suppressed the increased production of superoxide anions (O[subscript 2]-) and phosphorylation of cPLA[subscript 2] induced by A[beta][subscript 42]. In addition, hydrolyzed products of cPLA[subscript 2], arachidonic acid (AA), but not lysophosphatidylcholine (LPC) caused astrocyte membranes to become more molecularly-ordered. These results suggest (1) a direct interaction of A[beta][subscript 42] with cell membranes making them more molecularly-disordered, and (2) A[beta][subscript 42] indirectly makes membranes become more molecularly-ordered by triggering the signaling pathway involving NADPH oxidase and cPLA[subscript 2].