Knock-in rats with homozygous PSEN1L435F Alzheimer mutation are viable and show selective γ-secretase activity loss causing low Aβ40/42 and high Aβ43

Luciano D'Adamio,Marc D Tambini

doi:10.1074/jbc.ra120.012542

Abstract

Familial forms of Alzheimer's disease (FAD) are caused by mutations in the gene encoding amyloid precursor protein, whose processing can result in formation of β-amyloid (Aβ). FAD can also result from mutations in the presenilin 1/2 (PSEN1/2) genes, whose protein products partially compose the γ-secretase complex that cleaves Aβ from amyloid precursor protein fragments. Psen1 KO mice and knock-in (KI) mice with homozygous FAD-associated L435F mutations (Psen1LF/LF) are embryonic and perinatally lethal, precluding a more rigorous examination of the effect of Alzheimer's disease–causing Psen1 mutations on neurodegeneration. Given that the rat is a more suitable model organism with regard to surgical interventions and behavioral testing, we generated a rat KI model of the Psen1LF mutation. In this study, we focused on young Psen1LF rats to determine potential early pathogenic changes caused by this mutation. We found that, unlike Psen1LF/LF mice, Psen1LF/LF rats survive into adulthood despite loss of γ-secretase activity. Consistent with loss of γ-secretase function, Psen1LF/LF rats exhibited low levels of Aβ38, Aβ40, and Aβ42 peptides. In contrast, levels of Aβ43, a longer and potentially more amyloidogenic Aβ form, were significantly increased in Psen1LF/LF and Psen1LF/w rats. The longer survival of these KI rats affords the opportunity to examine the effect of homozygous Psen1 Alzheimer's disease–associated mutations on neurodegeneration in older animals.

Highlights

Familial forms of Alzheimer’s disease (FAD) are caused by mutations in the gene encoding amyloid precursor protein, whose processing can result in formation of ␤-amyloid (A␤)
Unlike Psen1LF/LF mice, Psen1LF/LF rats survive into adulthood despite loss of ␥-secretase activity
The Psen1 L435F mutation was selected, given its profound alteration of amyloid precursor protein (APP) metabolism [8] and age-dependent neurodegenerative changes seen in KI Psen1LF mice [7]

Summary

Introduction

Familial forms of Alzheimer’s disease (FAD) are caused by mutations in the gene encoding amyloid precursor protein, whose processing can result in formation of ␤-amyloid (A␤). C, levels of Psen2 RNA from brain lysate were measured in Psen1w/w, Psen1LF/w, and Psen1LF/LF P0 rats by quantitative RT-PCR and normalized to Gapdh levels.

Results

Conclusion