The influence of the carboxyl terminus of the Alzheimer Aβ peptide on its conformation, aggregation, and neurotoxic properties

Brian Soreghan, Christian Pike, Rakez Kayed, Wenquiang Tian, Saskia Milton, Carl Cotman, Charles G. Glabe

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)81-94
Number of pages14
JournalNeuroMolecular Medicine
Issue number1
StatePublished - 2002
Externally publishedYes


  • Aggregation
  • Amyloid Aβ
  • Fibril formation
  • Neurotoxicity

ASJC Scopus subject areas

  • Molecular Medicine
  • Neurology
  • Cellular and Molecular Neuroscience


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