a-tailored-hplc-purification-protocol-that-yields-high-purity-amyloid

A Tailored HPLC Purification Protocol That Yields High-purity Amyloid Beta 42 and Amyloid Beta 40 Peptides, Capable of Oligomer Formation

Amyloidogenic peptides such as the Alzheimer's disease-implicated Amyloid beta (A&#946;), can present a significant challenge when trying to obtain high ...

University of California, Santa Cruz

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.

Introduction of d-Glutamate at a Critical Residue of Aβ42 Stabilizes a Prefibrillary Aggregate with Enhanced Toxicity.

Amyloid beta-protein 42 plays an important role in the onset and progression of Alzheimer's disease. Familial mutations have identified the glutamate residue 22 as a hotspot with regard to peptide neurotoxicity. We introduce an approach to study the influence of systematic sidechain modification at this residue, employing chirality as a structural probe. Circular dichroism experiments reveal that charge-preserving alterations of the amino acid sidechain attenuate the characteristic random coil to β-sheet transition associated with the wildtype peptide. Removal of the negative charge from residue 22, a trait observed with all known familial mutations at this residue, gives rise to a peptide with limited random coil propensity and high β-sheet characteristics. Our approach can be extended to other residues of Aβ, as well as further amyloidogenic peptides.

Article	Year
Introduction of d-Glutamate at a Critical Residue of Aβ42 Stabilizes a Prefibrillary Aggregate with Enhanced Toxicity. Chemistry (Weinheim an der Bergstrasse, Germany)\| PubMed ID: 27272258	2016
Using chiral peptide substitutions to probe the structure function relationship of a key residue of Aβ42. Chirality\| PubMed ID: 27933649	2017

Alejandro R. Foley

Biography

JoVE Journal Publications

Other Publications