Catalytically active tissue transglutaminase colocalises with Aβ pathology in Alzheimer's disease mouse models.

Micha M M Wilhelmus,Benjamin Drukarch,Mieke De Jager,August B Smit,Rolinka J Van Der Loo

doi:10.1038/srep20569

Abstract

Alzheimer’s disease (AD) is characterised by amyloid-beta (Aβ) protein deposition in the brain. Posttranslational modifications in Aβ play an important role in Aβ deposition. Tissue transglutaminase (tTG) is an enzyme involved in posttranslational cross-linking of proteins. tTG levels and activity are increased in AD brains, and tTG is associated with Aβ deposits and lesion-associated astrocytes in AD cases. Furthermore, Aβ is a substrate of tTG-catalysed cross-linking. To study the role of tTG in Aβ pathology, we compared tTG distribution and activity in both the APPSWE/PS1ΔE9 and APP23 mice models with human AD. Using immunohistochemistry, we found association of both tTG and in situ active tTG with Aβ plaques and vascular Aβ, in early and late stages of Aβ deposition. In addition, tTG staining colocalised with Aβ-associated reactive astrocytes. Thus, alike human AD cases, tTG was associated with Aβ depositions in these AD models. Although, distribution pattern and spatial overlay of both tTG and its activity with Aβ pathology was substantially different from human AD cases, our findings provide evidence for an early role of tTG in Aβ pathology. Yet, species differences should be taken into account when using these models to study the role of tTG in Aβ pathology.

Highlights

At present, knowledge concerning the expression, activity and distribution of tTG in Alzheimer’s disease (AD) is derived from post mortem human brain material and cerebrospinal fluid[9,10,18,19,20,21]
We describe for the first time the association of tTG with Aβ pathology in two different AD mouse models
The general distribution pattern of tTG in mice was similar to our observations in human brain, the association of tTG and in situ active tTG with Aβ pathology differed between the mouse models and human AD cases

Summary

Introduction

Knowledge concerning the expression, activity and distribution of tTG in AD is derived from post mortem human brain material and cerebrospinal fluid[9,10,18,19,20,21] This provides valuable information on the possible role of tTG in Aβ pathology, investigating whether tTG might be a potential target to counteract Aβ pathology requires suitable animal models that mimic both the distribution and activity of tTG in development of Aβ pathology as observed in AD cases. As we were interested in the role of tTG in AD pathology and in particular Aβ aggregation and accumulation, in the present study we investigated whether the distribution of tTG and in situ activity in these AD mouse models at different stages of Aβ pathology is similar to our observations in human AD cases For this purpose, we used immunohistochemistry and an in situ tTG activity assay on post-mortem tissue sections

Methods

Results

Conclusion