Even though there is compelling evidence for a causal role of amyloid forming proteins in disease, the type of amyloid and its assembly state is controversial and remains to be established. Prefibrillar amyloid oli- gomers are soluble spherical aggregates of approximately 3-10 nm in diameter that have been observed for many different types of amyloids by electron and atomic force microscopy. One of the significant advances in our understanding of prefibrillar oligomers was the finding that amyloid oligomers have a common peptide backbone structure that is distinct from amyloid fibrils based on the observation that a conformation depend- ent antibody specifically recognizes a common epitope on amyloid oligomers, but not fibrils, monomers or natively folded proteins for many different types of proteins. This indicates that the antibody recognizes a ge- neric polypeptide backbone epitope that is independent of the amino acid sequence, but yet is shared in common among all types of amyloid oligomers. The anti-oligomer antibody also generically inhibits the toxic- ity of soluble oligomers examined in vitro. Since different amyloid oligomers share a common structure and they are generically toxic to cells regardless of what protein they are derived from, this suggests that they have the same primary mechanism of toxicity in degenerative diseases. A growing body of evidence sug- gests that membrane permeabilization by amyloid oligomers may represent the common, primary mecha- nism of pathogenesis of amyloid related degenerative diseases. The overall goal of this program project is to elucidate the mechanism of membrane permeabilization by amyloid prefibrillar oligomers. I support of the specific aims of the projects, Core C will provide homogene- ous preparations of prefibrillar Aft oligomers to the projects as well as fluorescent and deuterated Aftoli- gomers. Core C will also provide preparations of alternative assembly states, such as amyloid fibrils and an- nular protofibrils as controls. Core C also provides conformation dependent antibodies that specifically rec- ognize prefibrillar oligomers, fibrils and annular protofibrils for use in blocking membrane permeabilization and verifying the conformational status of the oligomer preparations during and after the experiments.

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National Institute on Aging (NIA)
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Bereau, Tristan; Wang, Zun-Jing; Deserno, Markus (2014) More than the sum of its parts: coarse-grained peptide-lipid interactions from a simple cross-parametrization. J Chem Phys 140:115101
Gericke, Arne; Leslie, Nicholas R; Lösche, Mathias et al. (2013) PtdIns(4,5)P2-mediated cell signaling: emerging principles and PTEN as a paradigm for regulatory mechanism. Adv Exp Med Biol 991:85-104
Lioudyno, Maria I; Birch, Alexandra M; Tanaka, Brian S et al. (2013) Shaker-related potassium channels in the central medial nucleus of the thalamus are important molecular targets for arousal suppression by volatile general anesthetics. J Neurosci 33:16310-22
Budvytyte, Rima; Valincius, Gintaras; Niaura, Gediminas et al. (2013) Structure and properties of tethered bilayer lipid membranes with unsaturated anchor molecules. Langmuir 29:8645-56
Shenoy, Siddharth S; Nanda, Hirsh; Lösche, Mathias (2012) Membrane association of the PTEN tumor suppressor: electrostatic interaction with phosphatidylserine-containing bilayers and regulatory role of the C-terminal tail. J Struct Biol 180:394-408
Shenoy, Siddharth; Shekhar, Prabhanshu; Heinrich, Frank et al. (2012) Membrane association of the PTEN tumor suppressor: molecular details of the protein-membrane complex from SPR binding studies and neutron reflection. PLoS One 7:e32591
Zan, Goh Haw; Tan, Cheemeng; Deserno, Markus et al. (2012) Hemifusion of giant unilamellar vesicles with planar hydrophobic surfaces: a fluorescence microscopy study. Soft Matter 8:10877-10886
Lioudyno, Maria I; Broccio, Matteo; Sokolov, Yuri et al. (2012) Effect of synthetic aýý peptide oligomers and fluorinated solvents on Kv1.3 channel properties and membrane conductance. PLoS One 7:e35090
Bereau, Tristan; Deserno, Markus; Bachmann, Michael (2011) Structural basis of folding cooperativity in model proteins: insights from a microcanonical perspective. Biophys J 100:2764-72
Yaron, Peter N; Holt, Brian D; Short, Philip A et al. (2011) Single wall carbon nanotubes enter cells by endocytosis and not membrane penetration. J Nanobiotechnology 9:45

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