In the diagnostic settings of Alzheimer’s disease, tau levels are commonly measured in CSF. These fluid tau levels correlate with the presence of tau pathology (clumps of tau proteins) in the brain. Regardless, CSF biomarkers for specific cellular disease processes are lacking for dementias related to tau clumping like Alzheimer’s disease and frontotemporal dementia.
From bench to bedside
As shown in previous work of the research group, neurons with tau clumps activate a stress response. In this translational study, Wolzak and her colleagues aimed to identify CSF biomarkers reflecting early tau pathology-associated unfolded protein response (UPR) activation. In short, this study stretches from a discovery in the lab all the way to dementia patients.
PDI as novel biomarker
In this project, the researchers first employed neurons in a culture dish and used mass spectrometry to determine which proteins they secrete when this response is active. In this way, they discovered that Protein Disulfide Isomerase (PDI) proteins are secreted by neurons with UPR activation and tau clumps. Next, they determined the levels of PDI in more than 1000 CSF samples from dementia patients gathered in different countries. This demonstrated that PDI levels are increased in patients with tau clumps in the brain. In conclusion, this study identifies PDI as a potential biomarker for monitoring the response to therapy in patients with dementia related to tau pathology.