TY  - JOUR
AU  - Poojari, Chetan
TI  - Aggregation of Amyloids at Biomembranes and its Implications in Alzheimers's Disease and Type II Diabetes
JO  - Biophysical journal
VL  - 104
IS  - 2
SN  - 0006-3495
CY  - New York, NY
PB  - Rockefeller Univ. Press
M1  - FZJ-2015-04474
SP  - 592a -
PY  - 2013
AB  - 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.
LB  - PUB:(DE-HGF)16
UR  - <Go to ISI:>//WOS:000316074305536
DO  - DOI:10.1016/j.bpj.2012.11.3291
UR  - https://juser.fz-juelich.de/record/202185
ER  -