Bioluminescence imaging of Aβ deposition in bigenic mouse models of Alzheimer's disease

Abstract

The undersigned authors wish to note, "The KefFC system of E. coli is maintained in an inactive state by the binding of glutathione (GSH) and is activated by the formation of GSH adducts (GSX), particularly those with bulky substituents. We described two crystal structures with density present in the ligand-binding domain that we interpreted as GSH and GSX. Recently, an independent, experienced crystallographer, who had viewed the structures from our study in a different context, made representations to us that cast doubt on position of the succinimido ring of GSX. We have further reviewed the density maps with the aid of an experienced crystallographer. As a consequence, we believe it is important to draw this altered interpretation of the crystal structures to the attention of readers. In both structures, the density for the backbone of GSH is clear and allows unequivocal assignment of the position of the tripeptide. In PDB coordinate set 3L9X, the density for the succinimido ring is very weak, making interpretation very speculative and the assignment rests on the identity of the ligand added to the crystallization mixture, for which there are two diastereomers in the solutiona possibility that provides some basis for weakening the density. However, in 3L9W there are two anomalies that affect the interpretation of the bound ligand. First, there is no density for the carbon atom attached to the sulfur of GSH and second, there is extra density adjacent to the position of sulfur that could be modelled as a constrained succinimido ring. However, this density could also be water or any other molecule that is trapped in the structure. Thus, while there is good evidence for the peptide, the evidence that it is in the GSH form is uncertain."There are no new data on either the structures or on the gating mechanism. However, we believe that we should be cautious in interpreting the structural data and that the field in general should be made aware of the alternative views of the electron density data. Note that the mutagenesis and spectroscopic data that were presented in the original manuscript are not affected by this alternative interpretation." Tarmo P. The authors note that the following grant should be added to the Acknowledgments: "NIH Grant AG002132." The authors note "The method used for exogenous expression of Ca V 1.2 channels in ref. 32 was incorrectly described as 'viral transduction' in the text. In fact, Yang et al. created transgenic mice with inducible, cardiomyocyte-specific expression of exogenous Ca V 1.2 channels regulated by a tetracycline-inducible promoter. When crossed with a transgenic mouse line expressing doxycycline-regulated reverse transcriptional activator under control of the α-myosin heavy chain protomer, the resulting double transgenic offspring expressed exogenous Ca V 1.2 channels in their cardiac myocytes after treatment with doxycycline. The authors regret the error in describing these methods."www.pnas.org/cgi

Transmission of multiple system atrophy prions to transgenic mice

“…Previously, we demonstrated that neurodegeneration can be monitored in living mice by performing bioluminescence imaging (BLI) on the brains of Tg(Gfap-luc) mice (29,30). In these mice, neurodegeneration triggers reactive astrocytic gliosis, resulting in a concomitant increase in Gfap transcription, which can be quantified using BLI.…”

Biaryl Amides and Hydrazones as Therapeutics for Prion Disease in Transgenic Mice

“…BLI has proved useful in monitoring neurodegeneration in various Tg mouse models (Keller et al, 2009;Tamgüney et al, 2009;Watts et al, 2011). Here we demonstrate that it can be used to predict drug efficacy before extension in survival is evident.…”

Mouse Models for Studying the Formation and Propagation of Prions

“…This obstacle has been overcome by performing BLI of A␤ plaque-associated astrocytic gliosis. Bigenic mice expressing both mutant human APP and a luciferase reporter driven by the Gfap promoter exhibit an age-dependent increase in the brain BLI signal, which can be accelerated by intracerebral inoculation with A␤ aggregatecontaining samples (72,73). Induction of Tau deposition by intracerebral injection of brain homogenate from either aged Tg mice expressing mutant human Tau or patients with various tauopathies has been observed in Tg mice expressing WT human Tau, which do not spontaneously develop Tau aggregates in their brains (74,75).…”