The signal peptide of the amyloid precursor protein forms amyloid-like aggregates and enhances Aβ42 aggregation

Abstract

Signal sequences are short peptides at the N terminus of proteins destined for the secretion pathway. Typically, after cleavage by peptidases, signal peptides are degraded by intra-membrane proteases. In some cases, however, signal peptides can be processed further and released into the endoplasmic reticulum, secretion pathways, or cytoplasm. The consequences of these processes remain unclear, in particular considering that dysregulated signal peptides could potentially aggregate and induce cytotoxicity. To investigate this problem, we study the signal peptide of the amyloid precursor protein (APP), which originates the Alzheimer’s β-amyloid (Aβ) peptide. Our results show that this signal peptide (residues 1–17 of APP [APP 1–17 SP]) can form amyloid-like cytotoxic aggregates. We further demonstrate that APP 1–17 SP seeds promote aggregation of Aβ, which raises the intriguing possibility of an interplay between APP 1–17 SP and Aβ aggregation in disease processes. The signal peptide of APP (APP 1–17 SP) self-assembles into amyloid-like aggregates APP 1–17 SP aggregates exhibit amyloid-like morphologies in SEM, TEM, and AFM APP 1–17 SP aggregates are cytotoxic to human SH-SY5Y and red blood cells APP 1–17 SP seeds augment Aβ42 aggregation Protein aggregation is associated with the pathogenesis of several human diseases. Gadhave et al. report that the signal peptide of the amyloid precursor protein (APP) can self-assemble into cytotoxic amyloid-like aggregates and enhance aggregation of the β-amyloid (Aβ) peptide, which forms amyloid plaques in Alzheimer’s disease.