Deletion of Presenilin 1 Hydrophilic Loop Sequence Leads to Impaired γ-Secretase Activity and Exacerbated Amyloid Pathology

Abstract

γ-Secretase processing of the amyloid precursor protein (APP) generates Aβ ₄₀ and Aβ ₄₂, peptides that constitute the principal components of the β-amyloid plaque pathology of Alzheimer's disease (AD). The γ-secretase activity is executed by a high-molecular-weight complex of which presenilin 1 (PS1) is an essential component. PS1 is a multi-pass membrane protein, and the large hydrophilic loop domain between transmembrane domains 6 and 7 has been shown to interact with various proteins. To determine the physiological function of the loop domain, we created a strain of PS1 knock-in mice in which the exon 10, which encodes most of the hydrophilic loop sequence, was deleted from the endogenous PS1 gene. We report here that the homozygous exon 10-deleted mice are viable but exhibit drastically reduced γ-secretase cleavage at the Aβ ₄₀, but not the Aβ ₄₂, site. Surprisingly, this reduction of Aβ ₄₀ is associated with exacerbated plaque pathology when expressed on APP transgenic background. Thus, the PS1 loop plays a regulatory role in γ-secretase processing, and decreased Aβ ₄₀, not increased Aβ ₄₂ is likely the cause for the accelerated plaque deposition in these animals. Our finding supports a protective role of Aβ ₄₀ against amyloid pathology and raises the possibility that impaired γ-secretase activity could be the basis for AD pathogenesis in general.