PEGylated phospholipid nanomicelles interact with beta-amyloid((1-42)) and mitigate its beta-sheet formation, aggregation and neurotoxicity in vitro.
beta-Amyloid (Abeta) is a hydrophobic peptide that drives the pathogenesis of Alzheimer's disease (AD) due to its aberrant aggregation. Inhibition of Abeta aggregation process is one of the most promising strategies for therapeutic intervention in AD. Here, we demonstrate that sterically stabilized (PEGylated) phospholipid nanomicelles (SSM) are effective in mitigating Abeta-42 aggregation using several deterministic techniques such as (1) Turbidimetry (2) Congo red binding (3) Thioflavine-T binding (4) Laser light scattering and (5) Electron Microscopy. alpha-Helicity of Abeta-42 is significantly augmented in the presence of SSM as demonstrated by circular dichroism (p<0.05). Cytotoxicity studies, employing human neuroblastoma SHSY-5Y cells, established that PEGylated phospholipid associated peptide demonstrated significantly lower neurotoxicity compared to lipid untreated Abeta-42 (p<0.05). Collectively, our results establish that PEGylated phospholipids abrogate transformation of Abeta-42 to amyloidogenic beta-sheeted form and impart neuroprotection in vitro. This study provides a foundation for designing nanoconstructs of PEGylated phospholipid nanomicelles in conjunction with a therapeutic agent for multitargeting the different pathophysiologies associated with AD.
Pai
Ashwini S
AS
Department of Biopharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA.
Rubinstein
Israel
I
Onyüksel
Hayat
H
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D008823:Micelles; D008954:Models, Biological; D053758:Nanoparticles / Q000737:chemistry*; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D010316:Particle Size; D010446:Peptide Fragments / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*; D010714:Phosphatidylethanolamines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010743:Phospholipids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D017433:Protein Structure, Secondary / Q000187:drug effects
C519184:1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000); D016229:Amyloid beta-Peptides; D008823:Micelles; D009498:Neurotoxins; D010446:Peptide Fragments; D010714:Phosphatidylethanolamines; D010743:Phospholipids; C075222:amyloid beta-protein (1-42); D011092:Polyethylene Glycols