The amyloid β-peptide (Aβ) is a 39-43 residue amphipathic peptide that is the major proteinaceous component of senile plaques that are characteristic of Alzheimer's disease (AD). To examine the contribution of the hydrophobic carboxyl-terminal domain on the aggregation, fibril formation, and neurotoxic activity, we have examined the effect of substituting the carboxyl-terminal residues 29-42 derived from two other type I transmembrane proteins: the β-adrenergic and low-density lipoprotein (LDL) receptor. The chimeric peptides, Aβ1-28ADR29-42 and Aβ1-28LDL29-42, have the same high β-sheet content as human Aβ1-42 in solution at pH 7.4 and display a conformation-dependent epitope that is associated with Aβ aggregates, indicating that these properties are largely independent of the carboxyl domain sequence. Previous studies have shown that the length of the carboxyl terminus is important for the formation of sodium dodecyl sulfate (SDS)-resistant oligomers. Aβ1-42 and the chimeric peptides co-assemble to form SDS-resistant, oligomeric mixed aggregates in all permutations, indicating that this interaction is not sequence specific. Upon assembly into insoluble aggregates, both chimeric peptides display an amorphous morphology rather than the regular 6-10 nm fibrils that are typical of human Aβ1-42. Aβ1-28ADR29-42 is equally toxic to primary rat hippocampal neurons as Aβ1-42, while Aβ1-28LDL29-42 is devoid of toxic activity. These results indicate that although β-sheet conformation may be required for toxic activity, it is not sufficient and 6-10 nm fibril morphology is not an obligate requirement for neuronal toxicity.
- Amyloid Aβ
- Fibril formation
ASJC Scopus subject areas
- Molecular Medicine
- Cellular and Molecular Neuroscience