Plasma membrane cholesterol controls the cytotoxicity of Alzheimer's disease AβP (1–40) and (1–42) peptides

Abstract

Cell degeneration in Alzheimer's disease is mediated by a toxic mechanism that involves interaction of the AβP peptide with the plasma membrane of the target cell. We report here that PC12 cells become resistant to the cytotoxic action of AβP when incubated in a medium that enriches cholesterol levels of the surface membrane. On the other hand, making cholesterol‐deficient membranes by either cholesterol extraction with cyclodextrin or by inhibiting de novo synthesis of cholesterol makes PC12 cells more vulnerable to the action of AβP. Increasing cholesterol content of PS liposomes also suppresses AβP‐dependent liposome aggregation. We suggest that by modifying the fluidity of the neuronal membranes, cholesterol modulates the incorporation and pore formation of AβP into cell membranes. This idea is supported by our finding that the enhanced cytotoxicity generated by lowering the membrane cholesterol content can be reversed by AβP calcium channel blockers Zn 2+ and tromethamine.—Arispe, N., Doh, M. Plasma membrane cholesterol controls the cytotoxicity of Alzheimer's disease AβP (1–40) and (1–42) peptides. FASEB J . 16, 1526–1536 (2002)