Introduction of d-Glutamate at a Critical Residue of Aβ42 Stabilizes a Prefibrillary Aggregate with Enhanced Toxicity.
The amyloid beta peptide 42 (Aβ42) is an aggregation-prone peptide that plays a pivotal role in Alzheimer's disease. We report that a subtle perturbation to the peptide through a single chirality change at glutamate 22 leads to a pronounced delay in the β-sheet adoption of the peptide. This was accompanied by an attenuated propensity of the peptide to form fibrils, which was correlated with changes at the level of the fibrillary architecture. Strikingly, the incorporation of d-glutamate was found to stabilize a soluble, ordered macromolecular assembly with enhanced cytotoxicity to PC12 cells, highlighting the importance of advanced prefibrillary Aβ aggregates in neurotoxicity.
Department of Chemistry and Biochemistry, Physical Science Building, University of California, 1156 High Street, Santa Cruz, USA.
Christopher J A
CJ
Warner
Department of Chemistry and Biochemistry, Physical Science Building, University of California, 1156 High Street, Santa Cruz, USA.
Subrata
S
Dutta
Department of Chemistry and Biochemistry, Physical Science Building, University of California, 1156 High Street, Santa Cruz, USA.
Alejandro R
AR
Foley
Department of Chemistry and Biochemistry, Physical Science Building, University of California, 1156 High Street, Santa Cruz, USA. jraskato@ucsc.edu.
Jevgenij A
http://orcid.org/0000-0002-0082-9113
JA
Raskatov
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D018698:Glutamic Acid / Q000737:chemistry*; D006801:Humans; D016716:PC12 Cells; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D051381:Rats
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D018698:Glutamic Acid
Alzheimer′s disease; aggregation; amyloid beta peptide; chirality; neurotoxicity