BAG1 Overexpression Stabilizes High Molecular Tau Protein – a Crucial Role of the Co-chaperone in Tau Pathology

Sandra Caecilie Signore,Pawel Kermer,Mathias Baehr,Fred Silvester Wouters,Matthias Schmitz

doi:10.11648/j.ajpn.20210902.18

Abstract

The Bcl-2-associated athanogene-1 (BAG1) exerts neuroprotective properties which has been shown in several studies of neurodegenerative disease models like Parkinson’s disease, Huntington’s disease and even cerebral ischemia. On the basis of the well-known neuroprotective function of the co-chaperone, we wanted to examine its properties in a model for Alzheimer’s disease, a neurological disorder of great significance. One of the hallmarks of Alzheimer’s disease, besides extracellular plaque formation, is the intra-neuronal accumulation of hyper-phosphorylated tau protein that leads to tau aggregation. When overexpressed together with a tau mutant with high propensity for aggregation, BAG1 led to the stabilization of high-molecular tau fragments in rat CSM 14.1 cells compared to wild-type cells. Deletion of the domain in BAG1 that is responsible for binding to Hsp70 (BAGΔC) abolished this effect, which could be confirmed by immunocytochemistry. In fact, BAG1 does not only increase mutant tau aggregation but also prevents its degradation by the proteasome. Immunochemistry revealed that overexpression of the Bcl-2-associated athanogene-1 gives rise to large tau aggregates surrounded by lysosomes. Furthermore, toxicity assays indicated increased tau toxicity in BAG1 overexpressing cells. Hence, in contrast to other neurodegenerative diseases, BAG1 seems to enhance Alzheimer´s pathology and to promote cell death due to the stabilization of aggregation-prone tau species that evade proteasomal clearance. To conclude, this analysis provides a new sight of the co-chaperone BAG1 and yet again demonstrates its complex influence in a model of Alzheimer’s disease.

Highlights

Bcl-2-associated athanogene-1 (BAG1) is the first identified member of the BAG family, a group of antiapoptotic proteins
We investigate the interaction of BAG1 and a specific mutant tau protein which has a high tendency for aggregation
We expected that BAG1 might have neuroprotective effects in tau pathology with respect to clearance of tau aggregates, but our results showed the opposite: BAG1 facilitates mutant tau aggregation leading to enhanced hyperphosphorylation within the cells and resulting in higher toxicity

Summary

Introduction

Bcl-2-associated athanogene-1 (BAG1) is the first identified member of the BAG family, a group of antiapoptotic proteins. It has been shown to be neuroprotective against stroke induced by middle cerebral artery occlusion in transgenic mice overexpressing BAG1 [14]. One of its vital functions could be shown in experiments with transgenic mice lacking BAG1 which died during embryonic development as a result of apoptosis in the nervous system and liver [15]. In line with these findings, overexpression of BAG1 provides protection against various apoptotic insults [11, 14, 16]. In models of Huntington’s disease [18] and Parkinson’s disease [19, 20], BAG1 proved to be neuroprotective

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