Amyloid-β peptide induces temporal membrane biphasic changes in astrocytes through cytosolic phospholipase A₂

Oligomeric amyloid-β peptide (Aβ) is known to induce cytotoxic effects and to damage cell functions in Alzheimer's disease. However, mechanisms underlying the effects of Aβ on cell membranes have yet to be fully elucidated. In this study, Aβ 1-42 (Aβ₄₂) was shown to cause a temporal biphasic change in membranes of astrocytic DITNC cells using fluorescence microscopy of Laurdan. Aβ₄₂ made astrocyte membranes became more molecularly-disordered within the first 30 min to 1 h, but gradually changed to more molecularly-ordered after 3 h. However, Aβ₄₂ caused artificial membranes of vesicles made of rat whole brain lipid extract to become more disordered only. The trend for more molecularly-ordered membranes in astrocytes induced by Aβ₄₂ was abrogated by either an NADPH oxidase inhibitor, apocynin, or an inhibitor of cytosolic phospholipase A₂ (cPLA₂), but not by an inhibitor of calcium-independent PLA₂ (iPLA₂). Apocynin also suppressed the increased production of superoxide anions (O₂^-) and phosphorylation of cPLA₂ induced by Aβ₄₂. In addition, hydrolyzed products of cPLA₂, arachidonic acid (AA), but not lysophosphatidylcholine (LPC) caused astrocyte membranes to become more molecularly-ordered. These results suggest (1) a direct interaction of Aβ₄₂ with cell membranes making them more molecularly-disordered, and (2) Aβ₄₂ also indirectly makes membranes become more molecularly-ordered by triggering the signaling pathway involving NADPH oxidase and cPLA₂ in astrocytes.