Endosomal pH favors shedding of membrane-inserted amyloid-β peptide.

Amyloid-β peptides (Aβs) are generated in a membrane-embedded state by sequential processing of amyloid precursor protein (APP). Although shedding of membrane-embedded Aβ is essential for its secretion and neurotoxicity, the mechanism behind shedding regulation is not fully elucidated. Thus, we devised a Langmuir film balance-based assay to uncover this mechanism. We found that Aβ shedding was enhanced under acidic pH conditions and in lipid compositions resembling raft microdomains, which are directly related to the microenvironment of Aβ generation. Furthermore, Aβ shedding efficiency was determined by the length of the C-terminal membrane-spanning region, whereas pH responsiveness appears to depend on the N-terminal ectodomain. These findings indicate that Aβ shedding may be directly coupled to its generation and represents an unrecognized control mechanism regulating the fate of membrane-embedded products of APP processing.