Javascript must be enabled for the correct page display

Tau phosphorylation: In Hibernation and Alzheimer’s

Klaver, K (2014) Tau phosphorylation: In Hibernation and Alzheimer’s. Bachelor's Thesis, Biology.

[img]
Preview
Text
Biol_Bc_2014_KoenKlaver.pdf - Published Version

Download (401kB) | Preview
[img] Text
akkoord_klaver.pdf - Other
Restricted to Repository staff only

Download (22kB)

Abstract

Tau is a MAP found in neurons. Tau hyperphosphorylation, which detaches tau from microtubules is one of the hallmarks of PHF’s observed in AD but is also observed in torpor where it is reversed after arousal without lasting neuronal damage. This review focusses on tau phosphorylation. We seek to understand the differences between tau phosphorylation in AD patients and tau phosphorylation in torpid animals in order to asses if reversal of tau phosphorylation, like during arousals, can treat tau pathology in AD. Human tau has an essential role in microtubule stability, intracellular transport and the release of neurotransmitters. When phosphorylated, tau detaches from microtubules. Phosphorylation is done by GSK3B, CDK5, CK1, PKA and many more kinases. PP2A is mostly responsible for the dephosphorylation of tau. AD is characterized by synaptic degeneration and extracellular SP’s, consisting of AB and intracellular tangles consisting of hyperphosphorylated tau. Tau phosphorylation but also deficiency of glucose metabolism correlates with disease progression. In AD increased GSK3B, CDK5, CK1, PSK1 activity and decreased PP2A activity is found. In vitro they can cause the phosphorylation of all residues found in AD tau. Due to its complexity the process of tau phosphorylation is still not completely understood and it remains to be proven if these kinases are solely responsible in vivo. During torpor tau is hyperphosphorylated by increased PKA and GSK3B activity and decreased PP2A activity. This is likely caused by temperature dependent activity shifts. During arousals animals quickly rewarm to euthermic state. Neuronal connections reappear and phosphorylation sites within tau’s MDB are rapidly dephosphorylated. Sites implicated in microtubule binding are phosphorylated in AD as well as during torpor. GSK3B activity is increased during AD and torpor possibly due to hypometabolism. Also PKA, CDK5, CK1 and PSK1 activity is increased in AD while in torpor only GSK3B and PKA are reported. Furthermore in AD the amount of phosphorylated tau slowly increases and is deposited into PHF’s while in hibernators tau is dephosphorylated during arousals. During torpor metabolic challenge and decreased temperature cause hyperphosphorylated tau which protects neurons from damage. The neurons of torpid animals do not have AB deposition and clear phosphorylated tau before irreversible damage occurs. Removing AB has failed to show significant efficacy in AD but GSK3B inhibition with lithium was found to partially reverse tau pathology. Mimicking what we learned from torpid animal decreasing kinase activity and increasing phosphatase activity could reverse tau phosphorylation partially or even fully and stop disease progression. This could ultimately restore the natural balance between kinase and phosphatase activity and lead to normal functioning tau but will unfortunately not be able to reverse the existing damage.

Item Type: Thesis (Bachelor's Thesis)
Degree programme: Biology
Thesis type: Bachelor's Thesis
Language: English
Date Deposited: 15 Feb 2018 07:56
Last Modified: 15 Feb 2018 07:56
URI: http://fse.studenttheses.ub.rug.nl/id/eprint/11632

Actions (login required)

View Item View Item