Abstract
Although there is compelling evidence that the beta amyloid peptide (Abeta) can be centrally involved in Alzheimer's disease, the natural role (if any) of this peptide remains unclear. Here we use green fluorescent protein (GFP) fusions to demonstrate that the Abeta sequence, like prion domains, can act as a modular aggregation domain when terminally appended to a normally soluble protein. We find that a single amino acid substitution (Leu(17) to Pro) in the beta peptide sequence can abolish this cis capacity to induce aggregation. Introduction of this substitution into full-length APP (i.e., a Leu(613)Pro substitution in APP695) alters the processing of APP leading to the accumulation of the C99 C-terminal fragment (CTF). We suggest that in at least some aggregation disease-related proteins the presence of an aggregation domain is not "accidental", but reflects a selected role of these domains in modulating the trafficking or metabolism of the parental protein.