Journal Article

FZJ-2015-04474

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Aggregation of Amyloids at Biomembranes and its Implications in Alzheimers's Disease and Type II Diabetes

Poojari, C. (Corresponding Author)FZJ*

2013
Rockefeller Univ. Press New York, NY

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Please use a persistent id in citations: doi:10.1016/j.bpj.2012.11.3291

Abstract: The aggregation of the amyloid-β peptide (Aβ) into neurotoxic oligomers on the neuronal membrane surface and its insertion into the membrane is considered to be a crucial event in the development of Alzheimer's disease (AD). However, the mechanism of insertion, pore formation and membrane disruption still needs to be uncovered. We used atomistic molecular dynamics (MD) simulations to investigate the behavior of Aβ in zwitterionic and anionic lipid bilayers. We studied the effect of Aβ secondary structure, oligomerization and mutation on its transmembrane stability and membrane maintenance. Our main finding is that β sheet-oligomerization is required for Aβto be stable in the membrane and to induce membrane permeabilization.Aggregation of human islet amyloid polypeptide (hIAPP) at beta-cell membranes is associated with the onset of type II diabetes. It is proposed that hIAPP aggregates induce cytotoxicity to the pancreatic islets of langerhans cells by membrane disruption. Chiral surface-specific vibrational sum frequency generation (SFG) spectroscopy in conjunction with ab initio simulations revealed a tilted orientation of hIAPP β sheet-aggregates at lipid/aqueous interfaces. We used this orientation for the starting structure of a hIAPP trimer inserted into a lipid bilayer and followed its effects on membrane maintenance using MD simulations. We observe β barrel-formation, which allows massive water and even ion flow across the membrane.

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Contributing Institute(s):

1. Strukturbiochemie (ICS-6)

Research Program(s):

1. 452 - Structural Biology (POF2-452) (POF2-452)

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Database coverage:
; BIOSIS Previews ; Current Contents - Life Sciences ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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