Histidine 131 in presenilin 1 is the pH-sensitive residue that causes the increase in Aβ42 level in acidic pH

Abstract

Alzheimer disease (AD) is the most common neurodegenerative disease worldwide. The pathological hallmark of AD is the presence of senile plaques in the brain, which are accumulations of amyloid-β peptide (Aβ) ending at the 42nd residue (i.e. Aβ42), which is produced through multistep cleavage by γ-secretase. Thus, methods to regulate γ-secretase activity to attenuate the production of Aβ42 are in urgent demand towards the development of treatments for AD. We and others have demonstrated that γ-secretase activity is affected by its localization and ambient environment. In particular, an increase in Aβ42 production is correlated with the intracellular transport of γ-secretase and endosomal maturation-dependent luminal acidification. In this study, we focused on the mechanism by which γ-secretase affects Aβ42 production together with alterations in pH. Histidine is known to function as a pH sensor in many proteins, to regulate their activities through the protonation state of the imidazole side chain. Among the histidines facing the luminal side of presenilin (PS) 1, which is the catalytic subunit of γ-secretase, point mutations at H131 had no effect on the Aβ42 production ratio in an acidic environment. We also observed an increase in Aβ42 ratio when histidine was introduced into N137 of PS2, which is the corresponding residue of H131 in PS1. These results indicated that H131 serves as the pH sensor in PS1, which contains γ-secretase, to regulate Aβ42 production depending on the luminal pH. Our findings provide new insights into therapeutic strategies for AD targeting endosomes or the intracellular transport of γ-secretase.