Apr 9, 2020

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

The Journal of Biological Chemistry
Marc D Tambini, Luciano D'Adamio

Abstract

Familial forms of Alzheimer's disease (FAD) are caused by mutations in the gene encoding amyloid precursor protein (APP), whose processing can result in the formation of amyloid β (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 APP fragments. Psen1-knockout (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 AD-causing Psen1 mutations on neurodegeneration. Given that the rat is a more suitable model organism with regards 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 the 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 ...Continue Reading

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Mentioned in this Paper

Regulation of Beta-amyloid Formation
Gamma-Secretase
PSEN1 gene
FAD
APP
Alzheimer's Disease
Genes
Nerve Degeneration
Knock-in
Operative Surgical Procedures

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