AD Tau Flashcards
LO
- Explain how Tau protein is abnormal in AD
- Suggest how abnormal Tau could cause neuronal dysfunction
- Understand how Tau causes degeneration and pathology spreads
- Based on the above identify suitable therapeutic interventions to counteract this
What is the current simplistic view on the link with amyloid, tau and neurodegeneration?
Amyloid problems –> Tau abnormalities –> neurodegeneration (simplistic view on where field is now. Is it too simple? Pros? Cons?)
What is the Tau pathology in?
What is this?
Neurofibrillary tangles
Neurofibrillary tangles (NFTs) are aggregates of hyperphosphorylated tau protein that are most commonly known as a primary biomarker of Alzheimer’s disease. Their presence is also found in numerous other diseases known as tauopathies.
Do mutations in the Tau gene cause AD?
Tell me evidence that has come to light about this statement?
Mutations in Tau gene DO NOT cause AD
No clear mutations that cause AD directly. Some individuals with trisomy of chromosome 17 (where Tau gene is) which have microduplications and these are an example of mutations, and these people can get AD disease. Therefore, making this statement not entirely correct due to recent findings
What do mutations in the Tau gene cause?
Mutations in the Tau gene cause Fronto-temporal dementia ch17
What is the only pathological entity in FTDP-17?
Tangle pathology
Abnormalities in tau –> to tangles –> neurodegeneration (nothing else is necessary)
What are Tauopathies?
Other neurodegenerative diseases with prominent tangle pathology identifies= Tauopathies
Tauopathies are neurodegenerative disorders characterized by the deposition of abnormal tau protein in the brain. The spectrum of tau pathologies expands beyond the traditionally discussed disease forms like Pick disease, progressive supranuclear palsy, corticobasal degeneration, and argyrophilic grain disease.
How is tau abnormal in AD and other tauopathies?
Neurofibrillary tangle…
- mutated in FTDP-1
- Hyperphosphorylated in all tauopathies
- Abnormalled expressed in FTD and AD
- Forms filaments in all tauopathies
Is tangle degradable?
What does it show?
The tangle is not degradable and remains and shows the outline of the neuron after neuronal death has occured
Tell me about the hyperphosphorylation in Tau proteins
Tau is highly phosphorylated (abnormal hyperphosphorylation- normal phosphorylation only occurs on residues that receive phosphate groups, PTM for localisation/ conformational change which could lead the protein becoming more or less active/ turnover of proteins. PTM control protein function and turnover. Phosphorylation is an example of PTM)
What % of Tau proteins are phosphorylated in AD?
100%
Tell me about experiments which have been done on gel motility and phosphorylation
High phosphorylation= heavier= retarded gel motility (shown on western blotting).
To prove the gel is retarded you could add a phosphatase and then run again
What do Tau aggregates form? What is this due to?
Tau aggregates to form filament structures- when highly phosphorylated when misfolded
How many isoforms of Tau are there?
6
How could these tau abnormalities cause neuronal dysfunction?
- Loss of normal physiological function
- Gain of toxic function
What effects does tau normally do in neurons?
Tau is a neuronal microtubule associated protein whose main biological functions are to promote microtubule self-assembly by tubulin and to stabilize those already formed. Tau also plays an important role as an axonal microtubule protein
Important role in maintaining microtubules
Plasticity relies on cytoskeleton to be broken down and reform
Tau binds to microtubule of cytoskeleton and keeps it stiff and intact
If highly phosphorylated the structure needed to bind to microtubule could be broken down
Can abnormal Tau affect the neuron?
- reducing binding to microtubules
- MT tracks collapse
- compromised axonal transport
- Disruption of synaptic connectivity
5.
What is the tau-MT hypothesis and what was done to test it?
For these reasons we first set out to ask how tau protein abnormalities, and in particular hyper-P tau, leads to clinical symptoms.
1. Make highly phosphorylated tau (p-tau)
2. This p-tau should not bind to the microtubules
- About 50% of Wt Tau binds to microtubules and they wanted to prove that highly p-tau reduced this binding
- Introduce LiCl and this makes the tau less phosphorylated, and this helps increase the tau binding to microtubules
3. The technique to study microtubular cytoskeleton is EM
- Intact MT on left. Cylindrical as they are intact prior to cutting them
- Right has highly p-tau and the EM image shows that there is a massive reduction of intact MT
4. Is this breakdown of cytoskeletal integrity effect axonal transport? To test this can add a marker
- Added GFP tag onto neuropeptide y (a NT)
- They found that in control fly with intact cytoskeletal integrity the NP y decorates axons
- In the fly with disrupted cytoskeletal integrity the NP y there’s gaps and pile ups. However, axon is still alive, this is known because they have moved along the axon they are just not as motile as they should be. Alive and highly dysfunctional
5. Synaptic defects
- Become dysfunctional
- Electrical impairment seen in muscles
6. Behavioural defects
- Don’t need neuron to die, just need the circuitry to become impaired to lead to these effects and cognitive impairment. Could run behavioural assay to test this (such as crawling assay or climbing assay)
- Or put maggots on back and see how long it would take them to turn themselves over
- And maggot racing to a yeast wall. Would take longer if expressing tau
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How does the disease spread?
What was the traditional view and what did they do to test this?
What is now the current view?
Traditional view: Braak staging
- 900 subjects ranging in age from 25-90 years
- Disease spread reflects clinical symptom
- What does this suggest?
- There is stereotypical spread of pathology across connected brain regions
- What does this imply?
- Stereotypical propagation of pathology through neural networks?
- Current view: cell-cell propagation
- Tau pathology starts in entorhinal cortex
When looking at how the disease spreads, what was the first in vivo demonstration done to look at cell to cell propagation?
Brain derived tau oligomers are what?
potent seeds inducing the aggregation and propagation of endogenous tau in vivo
Only mice injected with brain-derived tau oligomers displayed significant widespread tau pathology 11 months post injection. Tau pathology was detected using well established methods, including ThS and Gallyas silver, as well as immunohistochemistry using AT8 and HT7 antibodies. (a–f) NFT in the hippocampal CA1 region and frontal cortex. Positive staining with Gallyas silver, ThS, and AT8 (specific for Ser202/Thr205 phosphorylated tau) established the presence of hyperphosphorylated NFT deposits and the spreading of the pathology to areas far from the injection site (hippocampus). (g–j) HT7 staining (specific for human tau) was confined to the injection site (g), demonstrating that tau deposits in neighboring areas are comprised of endogenous murine tau and not derived from the original inocula. Scale bars 12mm
How do Tau aggregates act?
In a prion-like manner
