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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 [APP1–17SP]) can form amyloid-like cytotoxic aggregates. We further demonstrate that APP1–17SP seeds promote aggregation of Aβ, which raises the intriguing possibility of an interplay between APP1–17SP and Aβ aggregation in disease processes.

Original publication




Journal article


Cell Reports Physical Science

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