Title
Modulating Early Stage Amyloid Aggregates by Dipeptide Linked Perylenebisimides: Structure Activity Relationship, Inhibition of Fibril Formation in Human CSF and Aβ1-40
Author
Sayan Roy Chowdhury, S. N. Balaji, Subrata Mondal, Niranjan Meher, Vishal Trivedi, Parameswar Krishnan Iyer
Year
2018
Journal
ACS Applied Biomaterials
Abstract
Amyloid aggregation is observed in many neurodegenerative diseases but the formation of final plaque seldom correlates to the disease severity. Early and intermediate structures such as soluble oligomers are considered as primary toxic species in protein misfolding diseases specifically linked to Aβ in Alzheimer’s disease (AD). Two peptides linked perylenebisimide isomers (PAPAP and APPPA) were developed to study the structure-activity relationship with toxic Aβ oligomer in commercial Aβ as well as in human cerebrospinal fluid (CSF), diminish and inhibit them and prevent them to form toxic amyloid fibrils from an early stage. Self-aggregation of perylenebisimides enables to form nano/micro-objects that is used to interact with the hydrophobic regions of peptide and direct the peptide aggregation into an ‘off-pathway’ preventing mature fibril formation. Remarkably, one of the Ala-Phe dipeptides linked perylenebisimide isomer (APPPA) showed high selectivity toward Aβ oligomer and could also cross endothelial monolayer barrier (blood-brain barrier-BBB) efficiently than the other derivative (PAPAP). Kinetic ThT studies and AFM imaging provided strong proof of both the isomers being able to inhibit fibrillation of prefibrillar and oligomeric Aβ in both commercial Aβ1-40 peptide as well as in real human CSF sample. Further, a correlation has been built using pristine fluorescence of perylenebisimides, showing modulation and ‘oligo-blocking’. The obtained data provides clear evidence that the mutual aggregation between the modulator and amyloid aggregate becomes predominant compared to their individual aggregation. These results reinforce the development of structural platform design to diminish toxic oligomers, inhibit them and prevent forming toxic amyloid fibrils at an early stage.
Full Article
Instrument
J-815
Keywords
Circular dichroism, Secondary structure, Chemical stability, Aggregation, Biochemistry