The Presenilin-1 ΔE9 Mutation Results in Reduced γ-Secretase Activity, but Not Total Loss of PS1 Function, in Isogenic Human Stem Cells

Abstract

Presenilin 1 (PS1) is the catalytic core of γ-secretase, which\ncleaves type-1 transmembrane proteins including the amyloid precursor protein\n(APP). PS1 also has γ-secretase independent functions and dominant PS1\nmissense mutations are the most common cause of familial Alzheimer’s\ndisease (FAD). Whether PS1 FAD mutations are gain or loss-of-function remains\ncontroversial, primarily because most studies have relied on overexpression in\nmouse and/or non-neuronal systems. We used isogenic euploid human iPSC lines to\ngenerate and study an allelic series of PS1 mutations including heterozygous\nnull mutations and homozygous and heterozygous FAD PS1 mutations. Rigorous\nanalysis of this allelic series in differentiated, purified neurons allowed us\nto resolve this controversy and to conclude that FAD PS1 mutations, expressed at\nnormal levels in the appropriate cell-type, impair γ-secretase activity,\nbut do not disrupt γ-secretase independent functions of PS1. Thus, FAD\nPS1 mutations do not act as simple loss of PS1 function, but instead dominantly\ngain an activity toxic to some, but not all PS1 functions.