Human and rodent Alzheimer β‐amyloid peptides acquire distinct conformations in membrane‐mimicking solvents

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Abstract
The major constituent of senile plaques (one of the hallmark lesions of Alzheimer's disease) is a 42(43)-amino-acid polypeptide, termed the A4 or β-amyloid peptide. The β-amyloid peptide or A4 is derived from one or more larger β-amyloid precursor proteins. The precursor protein from whence the A4 peptide is derived is highly conserved throughout evolution, and humans, monkeys, dogs, and bears develop brain deposits of A4 peptide in amyloid fibrils. However, similar accumulations of A4 amyloid are negligible in the brains of rats and mice for reasons that remain unexplored. Notably, the A4 sequence of rodents, deduced from the cDNA clones, differs only in three amino acids from the A4 isolated from the brain of humans. Hence, these differences could account for the inability of rodents to develop Alzheimer-like A4 amyloid plaques. To test this hypothesis directly, using physical and chemical model systems, we synthesized, purified, and characterized A4 peptides corresponding to the human and rodent sequences. Circular dichroic and Fourier-transform infrared spectroscopy were used with various membrane-mimicking solvents, different peptide concentrations, and variable pH to identify those environmental conditions that promoted β-pleated sheet formation of the human versus rodent A4. At an intermediate alkaline pH (≤ 10), the rodent peptide has more β-pleated sheet structure than the human sequence. The β-pleated sheets for both peptides could be eliminated at very high pH (≥ 12). The amount of the β-structure increased in an octyl glucoside solution, compared to that found in SDS, as well as in several of the other solutions tested here. This suggests that particles originated from prior membrane damage may play a role in the stabilization of β-pleated sheets with subsequent formation of amyloid deposits. Finally, we found that higher β-pleated sheet content was observed for the rodent sequences in acetonitrile/water mixtures. In contrast, more β-pleated sheets were detected with the human A4 in trifluoroethanol/water mixtures at neutral pH. Remarkably, at relatively low peptide concentrations, only the human sequence assumed an extended secondary structure. These data suggest that subtle inter-species amino-acid differences may account for the inability of the rodent peptide to form amyloid fibrils in situ.

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