Overexpression of Glutaminyl Cyclase, the Enzyme Responsible for Pyroglutamate Aβ Formation, Induces Behavioral Deficits, and Glutaminyl Cyclase Knock-out Rescues the Behavioral Phenotype in 5XFAD Mice

Sadim Jawhar,Oliver Wirths,Stephan Schilling,Sigrid Graubner,Hans-Ulrich Demuth,Thomas A Bayer

doi:10.1074/jbc.m110.185819

Abstract

Pyroglutamate-modified Aβ (AβpE3-42) peptides are gaining considerable attention as potential key players in the pathology of Alzheimer disease (AD) due to their abundance in AD brain, high aggregation propensity, stability, and cellular toxicity. Overexpressing AβpE3-42 induced a severe neuron loss and neurological phenotype in TBA2 mice. In vitro and in vivo experiments have recently proven that the enzyme glutaminyl cyclase (QC) catalyzes the formation of AβpE3-42. The aim of the present work was to analyze the role of QC in an AD mouse model with abundant AβpE3-42 formation. 5XFAD mice were crossed with transgenic mice expressing human QC (hQC) under the control of the Thy1 promoter. 5XFAD/hQC bigenic mice showed significant elevation in TBS, SDS, and formic acid-soluble AβpE3-42 peptides and aggregation in plaques. In 6-month-old 5XFAD/hQC mice, a significant motor and working memory impairment developed compared with 5XFAD. The contribution of endogenous QC was studied by generating 5XFAD/QC-KO mice (mouse QC knock-out). 5XFAD/QC-KO mice showed a significant rescue of the wild-type mice behavioral phenotype, demonstrating the important contribution of endogenous mouse QC and transgenic overexpressed QC. These data clearly demonstrate that QC is crucial for modulating AβpE3-42 levels in vivo and prove on a genetic base the concept that reduction of QC activity is a promising new therapeutic approach for AD.

Highlights

Besides full-length A␤ 40 and 42 isoforms starting with an aspartate at position 1, a variety of different N-truncated A␤ peptides have been identified in Alzheimer disease (AD) brains
Because the expression of the human QC (hQC) trangene is driven by the Thy1 promoter, abundant pyramidal neurons expressing hQC were detected in various brain regions of hQC and 5XFAD/hQC mice including the cortex (Fig. 1, A–D), the hippocampus (Fig. 1, E and F), the midbrain and the cerebellum
It has been demonstrated that QC inhibition significantly reduced A␤pE3 formation in vivo, emphasizing the importance of QC activity during cellular maturation of pyroglutamate-containing peptides

Summary

Introduction

Besides full-length A␤ 40 and 42 isoforms starting with an aspartate at position 1, a variety of different N-truncated A␤ peptides have been identified in AD brains. Oral application of a QC inhibitor resulted in reduced A␤pE3– 42 burden in two different transgenic mouse models of AD as well as in a transgenic Drosophila model. Treatment of these mice was accompanied by reductions in A␤x-40/42, diminished plaque formation and gliosis, as well as improved performance in context memory and spatial learning tests [10]. The contribution of QC was studied for the first time using genetic means by human QC overexpression and endogenous QC-knock-out in an AD mouse model

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