College of Science

Paul Nerenberg [Caltech]

SEMINAR — A physical approach to understanding Alzheimer's disease: molecular simulations of amyloid beta secretion

May 21, 2015 10:50 AM to May 21, 2015 12:00 PM at Building 8, Room 241

alpha-beta-42Amyloid beta (Aβ) is a peptide that has been implicated as the main causative agent in Alzheimer's disease. Although several disease-accelerating mutations have been identified, the top risk factor for Alzheimer's disease is a person's age, and it remains unclear why this is so. One hypothesis is that the composition of neuronal cell membranes changes as we age and that these changes in composition alter the processing and subsequent secretion of Aβ from the cell membrane. Using a coarse-grained lipid and peptide model, we use molecular simulations to show that the stability of Aβ in model cell membranes depends on asymmetric distributions of cholesterol across the membrane leaflets. We find that a highly asymmetric cholesterol distribution that is depleted on the exofacial leaflet but enhanced on the cytofacial leaflet of the model membrane thermodynamically favors membrane retention of a fully embedded Aβ peptide. However, in the case of increased concentration of cholesterol on the exofacial leaflet, as is typical of aging or Alzheimer’s disease, the free energy profile favors extrusion of Aβ's highly reactive N-terminus into the extracellular space where it is available to disease-related processes.

10:50 a.m. Refreshments

11:00 a.m. Seminar

Building 8 - Room 241

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