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Phosphatidylethanolamine Enhances Amyloid Fiber-Dependent Membrane Fragmentation
Sciacca, Michele F. M.,Brender, Jeffrey R.,Lee, Dong-Kuk,Ramamoorthy, Ayyalusamy American Chemical Society 2012 Biochemistry Vol.51 No.39
<P>The toxicity of amyloid-forming peptides has been hypothesized to reside in the ability of protein oligomers to interact with and disrupt the cell membrane. Much of the evidence for this hypothesis comes from in vitro experiments using model membranes. However, the accuracy of this approach depends on the ability of the model membrane to accurately mimic the cell membrane. The effect of membrane composition has been overlooked in many studies of amyloid toxicity in model systems. By combining measurements of membrane binding, membrane permeabilization, and fiber formation, we show that lipids with the phosphatidylethanolamine (PE) headgroup strongly modulate the membrane disruption induced by IAPP (islet amyloid polypeptide protein), an amyloidogenic protein involved in type II diabetes. Our results suggest that PE lipids hamper the interaction of prefibrillar IAPP with membranes but enhance the membrane disruption correlated with the growth of fibers on the membrane surface via a detergent-like mechanism. These findings provide insights into the mechanism of membrane disruption induced by IAPP, suggesting a possible role of PE and other amyloids involved in other pathologies.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/bichaw/2012/bichaw.2012.51.issue-39/bi3009888/production/images/medium/bi-2012-009888_0008.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/bi3009888'>ACS Electronic Supporting Info</A></P>
Barry, Jeffrey,Fritz, Michelle,Brender, Jeffrey R.,Smith, Pieter E. S.,Lee, Dong-Kuk,Ramamoorthy, Ayyalusamy American Chemical Society 2009 JOURNAL OF THE AMERICAN CHEMICAL SOCIETY - Vol.131 No.12
<P>Curcumin is the active ingredient of turmeric powder, a natural spice used for generations in traditional medicines. Curcumin's broad spectrum of antioxidant, anticarcinogenic, antimutagenic, and anti-inflammatory properties makes it particularly interesting for the development of pharmaceutical compounds. Because of curcumin's various effects on the function of numerous unrelated membrane proteins, it has been suggested that it affects the properties of the bilayer itself. However, a detailed atomic-level study of the interaction of curcumin with membranes has not been attempted. A combination of solid-state NMR and differential scanning calorimetry experiments shows curcumin has a strong effect on membrane structure at low concentrations. Curcumin inserts deep into the membrane in a transbilayer orientation, anchored by hydrogen bonding to the phosphate group of lipids in a manner analogous to cholesterol. Like cholesterol, curcumin induces segmental ordering in the membrane. Analysis of the concentration dependence of the order parameter profile derived from NMR results suggests curcumin forms higher order oligomeric structures in the membrane that span and likely thin the bilayer. Curcumin promotes the formation of the highly curved inverted hexagonal phase, which may influence exocytotic and membrane fusion processes within the cell. The experiments outlined here show promise for understanding the action of other drugs such as capsaicin in which drug-induced alterations of membrane structure have strong pharmacological effects.</P>
Two-Step Mechanism of Membrane Disruption by Aβ through Membrane Fragmentation and Pore Formation
Sciacca, Michele F.M.,Kotler, Samuel A.,Brender, Jeffrey R.,Chen, J.,Lee, D.k.,Ramamoorthy, A. Biophysical Society ; Published for the Biophysica 2012 Biophysical journal Vol.103 No.4
Disruption of cell membranes by Aβ is believed to be one of the key components of Aβ toxicity. However, the mechanism by which this occurs is not fully understood. Here, we demonstrate that membrane disruption by Aβ occurs by a two-step process, with the initial formation of ion-selective pores followed by nonspecific fragmentation of the lipid membrane during amyloid fiber formation. Immediately after the addition of freshly dissolved Aβ<SUB>1-40</SUB>, defects form on the membrane that share many of the properties of Aβ channels originally reported from single-channel electrical recording, such as cation selectivity and the ability to be blockaded by zinc. By contrast, subsequent amyloid fiber formation on the surface of the membrane fragments the membrane in a way that is not cation selective and cannot be stopped by zinc ions. Moreover, we observed that the presence of ganglioside enhances both the initial pore formation and the fiber-dependent membrane fragmentation process. Whereas pore formation by freshly dissolved Aβ<SUB>1-40</SUB> is weakly observed in the absence of gangliosides, fiber-dependent membrane fragmentation can only be observed in their presence. These results provide insights into the toxicity of Aβ and may aid in the design of specific compounds to alleviate the neurodegeneration of Alzheimer's disease.
Yoo, Seong Il,Yang, Ming,Brender, Jeffrey R.,Subramanian, Vivekanandan,Sun, Kai,Joo, Nam Eok,Jeong, Soo‐,Hwan,Ramamoorthy, Ayyalusamy,Kotov, Nicholas A. WILEY‐VCH Verlag 2011 Angewandte Chemie Vol.123 No.22
<P><B>Die Bildung von Amyloidfibrillen</B> ist die Ursache für viele neurodegenerative Krankheiten wie Alzheimer. Medikamente können die Bildung von Fibrillen verhindern, indem sie an Amyloidpeptide binden. In der Zuschrift auf S. 5216 ff. berichten N. A. Kotov et al. über die hemmende Wirkung von Nanopartikeln, die an Amyloidoligomere binden. Die Nanopartikel zeigen einen ähnlichen Mechanismus der Hemmung wie Proteine, die die Bildung von Amyloidfibrillen im menschlichen Körper verhindern.</P>
Lee, Sanghyun,Zheng, Xueyun,Krishnamoorthy, Janarthanan,Savelieff, Masha G.,Park, Hyun Min,Brender, Jeffrey R.,Kim, Jin Hoon,Derrick, Jeffrey S.,Kochi, Akiko,Lee, Hyuck Jin,Kim, Cheal,Ramamoorthy, Ayy American Chemical Society 2014 JOURNAL OF THE AMERICAN CHEMICAL SOCIETY - Vol.136 No.1
<P>Alzheimer’s disease (AD) is characterized by multiple, intertwined pathological features, including amyloid-β (Aβ) aggregation, metal ion dyshomeostasis, and oxidative stress. We report a novel compound (<B><B>ML</B></B>) prototype of a rationally designed molecule obtained by integrating structural elements for Aβ aggregation control, metal chelation, reactive oxygen species (ROS) regulation, and antioxidant activity within a single molecule. Chemical, biochemical, ion mobility mass spectrometric, and NMR studies indicate that the compound <B><B>ML</B></B> targets metal-free and metal-bound Aβ (metal–Aβ) species, suppresses Aβ aggregation in vitro, and diminishes toxicity induced by Aβ and metal-treated Aβ in living cells. Comparison of <B><B>ML</B></B> to its structural moieties (i.e., 4-(dimethylamino)phenol (<B>DAP</B>) and (8-aminoquinolin-2-yl)methanol (<B>1</B>)) for reactivity with Aβ and metal–Aβ suggests the synergy of incorporating structural components for both metal chelation and Aβ interaction. Moreover, <B><B>ML</B></B> is water-soluble and potentially brain permeable, as well as regulates the formation and presence of free radicals. Overall, we demonstrate that a rational structure-based design strategy can generate a small molecule that can target and modulate multiple factors, providing a new tool to uncover and address AD complexity.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jacsat/2014/jacsat.2014.136.issue-1/ja409801p/production/images/medium/ja-2013-09801p_0008.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/ja409801p'>ACS Electronic Supporting Info</A></P>