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Department of Anatomy, Physiology and Genetics, and Institute for Molecular Medicine, Uniformed Services University School of Medicine, USUHS, Bethesda, Maryland, USA
1Correspondence: Department of Anatomy, Physiology and Genetics, School of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda MD, 20814, USA. E-mail: narispe{at}usuhs.mil
Cell degeneration in Alzheimer’s disease is mediated by a toxic mechanism that involves interaction of the AßP peptide with the plasma membrane of the target cell. We report here that PC12 cells become resistant to the cytotoxic action of AßP 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 AßP. Increasing cholesterol content of PS liposomes also suppresses AßP-dependent liposome aggregation. We suggest that by modifying the fluidity of the neuronal membranes, cholesterol modulates the incorporation and pore formation of AßP 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 AßP calcium channel blockers Zn2+ and tromethamine.—Arispe, N., Doh, M. Plasma membrane cholesterol controls the cytotoxicity of Alzheimer’s disease AßP (1–40) and (1–42) peptides.
Key Words: amyloid-ß-peptide • AßP ion channels • calcium • phosphatidylserine • membrane interaction
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