UPR activity as early biomarker for tauopathies

Amsterdam, Netherlands,

Grantees

Dr. Wiep Scheper

Organizations

VU Medical Centre

Project description

The majority of dementias, including Alzheimer’s disease, are characterized by accumulation of aggregates (“clumps”) of the protein tau. These age-related neurodegenerative diseases present an increasing socio-economic burden. However, to date, attempts to design a disease-modifying therapy have all failed in clinical trials. This indicates the urgent unmet need for novel and earlier biomarkers and alternative therapeutic targets, for both of which we propose that the unfolded protein response (UPR) has great potential. Our lab has demonstrated that the UPR is activated in brains of patients with the earliest stages of tau pathology, preceding neuronal loss. Recent evidence shows that UPR activity is transmitted from cell-to-cell.  Because neurons in the brains of patients with the earliest stages of tau pathology have an active UPR, they will also transmit UPR to other cells. This transmitted UPR (tUPR) activity may be present in body fluids. Here we aim to investigate the potential of tUPR activity in cerebrospinal fluid (CSF) or blood as an early biomarker for tauopathies.

Relevance to the acceleration of therapeutics for neurodegenerative diseases of aging

If the project is successful and tUPR activity can reliably be determined in the CSF, it could present an earlier marker than tau in CSF that is regarded as marker for neuronal loss. The results of this study can potentially be employed for identification of patients that can be enrolled in trials with tau or UPR-based interventions, as well as the subsequent monitoring of treatment efficacy and dose adjustment.

Anticipated outcome

In this project we expect to obtain results demonstrating whether tUPR activity has potential as as an early biomarker for tauopathies. If the results indicate this, a follow-up study will be initiated towards validation and implementation in clinical practice.