The role of copper ions and lipid membranes in Tau protein aggregation linked to neurodegenerative diseases
File(s)
Author(s)
Song, Cheng
Type
Thesis
Abstract
The tau protein, which is normally enriched in the neuron, is an intrinsically
disordered protein without a fixed structure. Physiologically, tau regulates the
dynamics of microtubules in the neuronal axon. Pathologically, the aggregation
of tau is a universally acknowledged phenomenon in Alzheimer’s disease.
There are two proposed risk factors of our interest to induce tau aggregation,
which are cupric ion (Cu2+) and lipid membranes. The presence of a high
concentration of Cu2+ in tau tangles has been verified through numerous post mortem assays. Previous studies indicated copper-dependent induction of
aggregates, suggesting the active role of copper ions. Reactive oxygen species
might be produced via Cu
2+/Cu+
redox cycling. On the other hand, lipid
membranes might template tau folding and aggregation.
Based on this background, I focus on the role of Cu2+ and lipid membrane in tau
aggregation and associated toxicity. In this thesis, I describe an investigation into
tau binding to Cu2+ in the concentration range of nanomolar and on the timescale
of milliseconds to tens of seconds by stopped flow kinetics. The binding affinity
was determined to be in the nanomolar regime. Cu2+ bound tau was also found
more prone to form toxic oligomers than tau alone via Thioflavin T assay.
In terms of the role of lipid membranes, the affinity between tau and two
physiological model lipid membrane systems is characterized. The affinity
between tau and lipid membranes is relatively high at acidic pH, suggesting that
the binding occurs in the lumen of vesicles. Tau could assemble on the diseased
lipid membrane and form a ring-like structure. The overnight incubation between
tau and lipid vesicles disrupts the integrity of membranes irreversibly.
These results may help decipher the early event of tau aggregation in the brain
and support therapeutic intervention against copper and lipid membranes as a
viable option.
disordered protein without a fixed structure. Physiologically, tau regulates the
dynamics of microtubules in the neuronal axon. Pathologically, the aggregation
of tau is a universally acknowledged phenomenon in Alzheimer’s disease.
There are two proposed risk factors of our interest to induce tau aggregation,
which are cupric ion (Cu2+) and lipid membranes. The presence of a high
concentration of Cu2+ in tau tangles has been verified through numerous post mortem assays. Previous studies indicated copper-dependent induction of
aggregates, suggesting the active role of copper ions. Reactive oxygen species
might be produced via Cu
2+/Cu+
redox cycling. On the other hand, lipid
membranes might template tau folding and aggregation.
Based on this background, I focus on the role of Cu2+ and lipid membrane in tau
aggregation and associated toxicity. In this thesis, I describe an investigation into
tau binding to Cu2+ in the concentration range of nanomolar and on the timescale
of milliseconds to tens of seconds by stopped flow kinetics. The binding affinity
was determined to be in the nanomolar regime. Cu2+ bound tau was also found
more prone to form toxic oligomers than tau alone via Thioflavin T assay.
In terms of the role of lipid membranes, the affinity between tau and two
physiological model lipid membrane systems is characterized. The affinity
between tau and lipid membranes is relatively high at acidic pH, suggesting that
the binding occurs in the lumen of vesicles. Tau could assemble on the diseased
lipid membrane and form a ring-like structure. The overnight incubation between
tau and lipid vesicles disrupts the integrity of membranes irreversibly.
These results may help decipher the early event of tau aggregation in the brain
and support therapeutic intervention against copper and lipid membranes as a
viable option.
Version
Open Access
Date Issued
2021-04
Date Awarded
2021-09
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Ying, Liming
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Masters
Qualification Name
Master of Philosophy (MPhil)