J.M. van der Harg
- Tau phosphorylation as adaptive response to metabolic dysfunction in the brain
- Award date
- 16 May 2017
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
In healthy neurons, tau is regulated by phosphorylation and dephosphorylation and fulfills multiple functions. However, in tauopathies tau is hyperphosphorylated resulting in the aggregation of the tau protein. To develop a successful therapeutic intervention understanding of the underlying mechanism of increased tau phosphorylation is essential. Therefore, the main goal of this thesis was to gain insight into the early underlying mechanism of increased tau phosphorylation in tauopathies. Increased tau phosphorylation is observed in tauopathies, but also during physiological metabolic stress situations like starvation and torpor. Remarkably, increased starvation- and torpor- induced tau phosphorylation is reversed upon return to a normal metabolic state. This indicates that metabolic dysfunction could induce hyperphosphorylation of tau. The unfolded protein response (UPR) is an adaptive response that can be activated upon metabolic stress. Increased tau phosphorylation in tauopathies might be regulated via the UPR. In this thesis, it is investigated whether increased tau phosphorylation like the UPR is an adaptive response to metabolic dysfunction in the brain of tauopathy patients that initially is neuroprotective, but might eventually results in irreversible pathological tau aggregates when metabolic homeostasis is not restored. The findings of this thesis provide evidence for: 1) glucose deprivation and insulin deficiency as trigger for increased tau phosphorylation, 2) hyperphosphorylated tau as an adaptive response, 3) different pathways like the UPR and PKA that regulate increased tau phosphorylation depending on the exposed neuronal stressor.
Thesis (complete) (Embargo up to and including 16 May 2019)
Chapter 3: The UPR reduces glucose metabolism via IRE1 signaling (Embargo up to and including 16 May 2019)
Chapter 5: Insulin deficiency results in reversible protein kinase A activation and tau phosphorylation (Embargo up to and including 16 May 2019)
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