Identification of the region of non‐Aβ component (NAC) of Alzheimer's disease amyloid responsible for its aggregation and toxicity

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Abstract
The non-beta-amyloid (Aβ) component of Alzheimer's disease amyloid (NAC) and its precursor α-synuclein have been linked to amyloidogenesis in several neurodegenerative diseases. NAC and α-synuclein both form β-sheet structures upon ageing, aggregate to form fibrils, and are neurotoxic. We recently established that a peptide comprising residues 3–18 of NAC retains these properties. To pinpoint the exact region responsible we have carried out assays of toxicity and physicochemical properties on smaller fragments of NAC. Toxicity was measured by the ability of fresh and aged peptides to inhibit the reduction of the redox dye 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) by rat pheochromocytoma PC12 cells and human neuroblastoma SHSY-5Y cells. On immediate dissolution, or after ageing, the fragments NAC(8–18) and NAC(8–16) are toxic, whereas NAC(12–18), NAC(9–16) and NAC(8–15) are not. Circular dichroism indicates that none of the peptides displays β-sheet structure; rather all remain random coil throughout 24 h. However, in acetonitrile, an organic solvent known to induce β sheet, fragments NAC(8–18) and NAC(8–16) both form β-sheet structure. Only NAC(8–18) aggregates, as indicated by concentration of peptide remaining in solution after 3 days, and forms fibrils, as determined by electron microscopy. These findings indicate that residues 8–16 of NAC, equivalent to residues 68–76 in α-synuclein, comprise the region crucial for toxicity.

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