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

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 /3-amyloid peptide. The B-amyloid peptide or A4 is derived from one or more larger P-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 B-pleated sheet formation of the human versus rodent A4. At an intermediate alkaline pH (< lo), the rodent peptide has more P-pleated sheet structure than the human sequence. The /I-pleated sheets for both peptides could be eliminated at very high pH ( 2 12). The amount of the p-structure increasedin 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 /3-pleated sheets with subsequent formation of amyloid deposits. Finally, we found that higher P-pleated sheet content was observed for the rodent sequences in acetonitrile/water mixtures. In contrast, more P-

Alzheimer’s Presenilin Mutation Sensitizes Neural Cells to Apoptosis Induced by Trophic Factor Withdrawal and Amyloid β-Peptide: Involvement of Calcium and Oxyradicals

“…The latter data suggest that PS-1 mutations may cause early onset AD by altering ␤APP processing in ways that lead to increased A␤ production. The increased vulnerability of neuronal cells expressing PS-1 L286V to A␤ toxicity and trophic factor withdrawal documented in the present study is unlikely to result from increased A␤ production because PC12 cells are a rat cell line and, in contrast to human A␤, rat A␤ is neither amyloidogenic nor neurotoxic (Otvos et al, 1993). However, it is conceivable that altered processing of ␤APP could reduce levels of neuroprotective secreted forms of APP, which have been shown to protect neurons against oxidative apoptotic insults, including A␤ toxicity and glucose withdrawal (Mattson et al, 1993b;Goodman and Mattson, 1994;Furukawa et al, 1996).…”

Amyloidogenicity of rodent and human βA4 sequences

“…Otvos et al have already suggested that subtle interspeties amino-acid differences may account for the inability of the rodent peptide to form amyloid fibrils in situ [32]. In contrast, other results showed no difference in solubility and secondary structure of the full-and shorter sized A4 peptides derived from humans and rodents [14].…”

Nicotine Inhibits Amyloid Formation by the β-Peptide

“…The -(1-28) peptide is an appropriate structural model for the complete -(1-42) peptide, since it produces soluble monomeric R-helical structures (Barrow & Zagorski, 1991;Otvos et al, 1993), as well as plaque-like oligomeric -sheet structures, similar to those found in natural amyloid plaques (Gorévic et al, 1987;Kirschner et al, 1987). The hydrophobic 29-42 region increases the rate of aggregation and -sheet production (Hilbich et al, 1991;Barrow et al, 1992;Burdick et al, 1992; but should not affect the ability of nicotine to bind to the -peptide.…”