Alzheimer's A42 and A40 peptides form interlaced amyloid fibrils

Deposition of amyloid (A) in the brain is a pathological hallmark of Alzheimer's disease. There are two major isoforms of A: the 42-residue A42 and the 40-residue A40. The only difference between A42 and A40 is that A42 has two extra residues at the C-terminus. The amyloid plaques in Alzheimer's brains consist of mostly A42 and some plaques contain only A42, even though A40 concentration is several-fold more than A42. Using electron paramagnetic resonance, we studied the formation of amyloid fibrils using a mixture of A42 and A40 in vitro. We show that A42 and A40 form mixed fibrils in an interlaced manner, although A40 is not as efficient as A42 in terms of being incorporated into A42 fibrils. Our results suggest that both A42 and A40 would be present in amyloid plaques if in vivo aggregation of A were similar to the in vitro process. Therefore, there must be some mechanisms that lead to the preferential deposition of A42 at the extracellular space. Identifying such mechanisms may open new avenues for therapeutic interventions to treat Alzheimer's disease.