Tau phosphorylation as adaptive response to metabolic dysfunction in the brain

J.M. van der Harg

Research output: ThesisResearch external, graduation externalAcademic

Abstract

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.
Original languageEnglish
Awarding Institution
  • University of Amsterdam
Supervisors/Advisors
  • Baas, Frank, Supervisor, External person
  • Scheper, Wiep, Co-supervisor
Award date16 May 2017
Publication statusPublished - 2017
Externally publishedYes

Cite this

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title = "Tau phosphorylation as adaptive response to metabolic dysfunction in the brain",
abstract = "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.",
author = "{van der Harg}, J.M.",
year = "2017",
language = "English",
school = "University of Amsterdam",

}

Tau phosphorylation as adaptive response to metabolic dysfunction in the brain. / van der Harg, J.M.

2017. 153 p.

Research output: ThesisResearch external, graduation externalAcademic

TY - THES

T1 - Tau phosphorylation as adaptive response to metabolic dysfunction in the brain

AU - van der Harg, J.M.

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

M3 - Research external, graduation external

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