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

Amyloid beta-peptide (A beta) is the major protein component in senile plaq ues of Alzheimer disease brain. The deposition of soluble A beta 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 A bet a(1-42) supported this view since A beta(1-42) became toxic to cultured cel ls only after an aging period during which fibrillar aggregates form. We re port in this paper that fibril formation itself, per se, is not sufficient to induce neurotoxicity and oxidative stress. Replacement of a single sulfu r atom from the methionine residue in the peptide with a methylene (CH2) st ill results in a peptide that forms fibrillar structures upon incubation, b ut 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 neurotoxic properties, but has no effect on the p eptide's ability to form fibrils. Replacement of the three histidine residu es of A beta(1-42) (one or more of which are proposed to be involved in Cu( II) binding, causing subsequent aggregation) with tyrosine (which has at le ast a 100-fold lower binding affinity for Cu(II) than histidine) altered ne ither the fibril formation nor the neurotoxic properties of the peptide. We propose that aggregation of A beta peptides, perhaps in concert with redox metal ions, forming a secondary structure conducive to sulfur-initiated ox idative stress, may be important in the neurotoxic properties of A beta(1-4 2).