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

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.