Sequential proteolytic cleavage of the Amyloid Precursor Protein (APP) by secretases (α, β, γ) generates beta-Amyloid peptide fragments, of which beta-Amyloid 1-42 forms a major component of amyloid plaques in neurons of Alzheimer’s disease (AD) brains.
Beta-Amyloid 1-28 is the most N-terminal Amyloid peptide fragment; it is water-soluble. Its three-dimensional structure reveals the folding of the peptide to form a predominantly a-helical structure with a bend centred on residue 12 with the side chains of histidine-13 and lysine-16 in close proximity, residing on the same face of the helix. This beta-Amyloid peptide fragment has a metal binding activity.
Beta-Amyloid 12-28 represents a binding site for apolipoprotein E (apoE). ApoE is a genetically inherited risk factor for AD that promotes aggregation of toxic Beta-Amyloid. This sequence encompasses a hydrophobic domain (residues 14–21) and a ß-turn (residues 22–28) which place two hydrophobic domains of Beta-Amyloid 14 to 21 and 29 to 40/42 opposite to each other, allowing for the assembly of Beta-Amyloid peptides into fibrils.
The secondary structure of Beta-Amyloid 12-28, a neutral peptide, is dominated by a-helix and random coil. The interaction of apoE with residues 12 to 28 of Beta-Amyloid is not just a non-specific hydrophobic interaction but plays a pivotal role in the mechanism of Beta-Amyloid pathology in AD. Beta-Amyloid 12-28 and several other fragments exhibit aggregation properties: they all contain either residues 17 to 20 or 30 to 35, indicating the importance of these regions for promoting aggregation of full-length Beta-Amyloid (1-42).