Alzheimer's amyloid βpeptide (1-42) fibrils are not always neurotoxic

Amyloid β-peptide (Aβ) is the major protein component in senile plaques of Alzheimer disease brain. The deposition of soluble Aβ peptide in the form of insoluble aggregates has been proposed to be an early step in the onset of the disease. Prior laboratory experiments with synthetic AβM2 supported this view since Aβi_42 became toxic to cultured cells only after an aging period during which fibrillar aggregates form. We report in this paper that fibril formation itself, perse, is not sufficient to induce neurotoxicity and oxidative stress. Replacement of a single sulfur atom from the methionine residue in the peptide with a méthylène (CH2) still results in a peptide that forms fibrillar structures upon incubation, but exhibits no toxicity or oxidative stress to cultured hippocampal neurons. Similarly, addition of the antioxidant vitamin E to the peptide abrogates its oxidative stress and heurotoxic properties, but has no effect on the peptide's ability to form fibrils. Replacement of the three histidine residues of Aβi_42 (one or more of which are proposed to be involved in Cu(ll) binding, causing subsequent aggregation) with tyrosine (which has at least a 100-fold lower binding affinity for Cu(ll) than histidine) altered neither the fibril formation nor the neurotoxic properties of the peptide. We propose that aggregation of Aβ peptides, perhaps in concert with redox metal ions, forming a secondary structure conducive to sulfur-initiated oxidative stress, may be important in the neurotoxic properties of AβM2.