Alzheimers disease Flashcards
what is a tauopathy?
We’ve got different tau protein fold presenting different diseases. Tauopathy Is where tau protein is highly and abnormally phosphorylated, becomes misfolded and accumulates to form different types of aggregates, lots of region-specific degeneration. Older brains are likely to get tauopathies. Even those with genetic mutations don’t get tauopathies and neurodegenerations young it happens all when their older.
-People who have tauopathy, 100% of their tau protein is phosphorylated.
what differences are seen in those who have AD (what protein is affected)?
where are this misfolded proteins found in AD and what is the spreading pattern?what chabges are seen in AD?
Misfolded tau protein looks different in different neuropathological diseases. Forms neurofibrillary tangles.
In AD it deposits in temporal cortex then spreading to parietal and frontal cortex via anatomically connceted brain circuits/pathways.
If you lose circuits in certain parts of brain like the frontal regions which is involved in personality changes, language, disinhibition (controlling your behaviour, physiological prevention of inappropriate behaviours) that if there was neurodegeneration in those regions you won’t have that disinhibition
what are good biomarkers for AD?
The use of biomarkers is good because it gives you a definitive answer of what the patient may have in terms of diseases rather than guessing what it may be. You can make up a biological change hence why biomarker is very useful and can measure.
Types of biomarkers you could use to distinguish disease is type of misfolded tau protein to see which disease they have. But you can also pick up phosphorylated tau as a starter indication of a neuropathological disease. Therefore, that could suggest that they are more likely to have a tauopathy instead of PD as in PD they don’t have tauopathies
what is the normal function of tau and what happens to the tau protein in AD?
Tau is important for maintaining stability of microtubules in axons of neurones and facilitating intracellular transport of molecules and organelles along axon of neurones such as neurotransmitters therefore important for synaptic connections(axonal transport). In AD, tau protein undergoes abnormal modifications and form aggregated in neurones which disrupt normal cellular function like destabilising microtubules disrupting neuronal signalling due to transport not being able to take place efficiently
-cell cytokeloten (cellular integrity impaired)
-vescile trafficking/ axonal transport affected
-organelle organisation wil be affeted as microtubles are destabilised
-neuronal activity du to lack of vescile fusion with memebrane therfroe signal trasnmission is reduced/affected
-neuroinflammation (prescence of misfoled tau triggers microglia-resident immune cell in brian to clear it but this can lead to prologned and chronic inflammation futher damaging neurones)
how can tau abnormalities cause neuronal dysfunction?
1)Dysfunction in tau’s role in stabilising microtubule in axons of neurones and axonal transport. So immediate implications include that phosphorylation of Tau makes it less likely to bind to microtubules, microtubules breakdown, thus axonal transport becomes comprised, which impairs synaptic transmissions.
Important to note that when tau is phosphorylates its ability to bind to microtubules declines
what does tau look like under electron microscopy?
EM looking the difference in functional tau and phosphorylated tau. It shows that having excessively phosphorylated tau protein destabilised the microtubules integrity which destabilise structural integrity of cell, breakdown of microtubules is shown as there’s reduced of black cylindrical structures.
If microtubes is breakdown upon hyperphosphorylation of tau protein, does this also breakdown axonal transport?
-yes
Which can lead to synaptic deficits
But these axons were still living which indicates dysfunction and not death. You could prove that via electrophysiology and behaviour tests
how can we counter abnormal tau mediated neuronal dysfunction?
-reduce tau phosphorl;ayion: kinase inhibitors
-microtubule stabilising agents
Can NAP rescue P-tau phenotypes? NAP is a microtubule stabiliser generated in lab, works like chemotherapy (in chemo microtubule stabilising drugs is required as cancer cells utilise microtubules for cell division using the mitotic spindles). Can nap restore broken-down microtubules and yes, the integrity of microtubules does get restored within 24 hrs or treatment. Drug name: Davuentid
As a result of that axonal transport deficits were improved thus synaptic transmission also improved. It targets microtubules in the brain so no peripheral side effects. This went to clinical trials and improved memory scores of those with mild cognitive impairment. Not effective for late stages as it gone beyond point of dysfunction and degeneration of neurones is more severe, can restore dead cells
larvae experiment
Larvae like to crawl on their bellies, via their motor neurones to turn themselves on their bellies if they were on their backs. So top column is functional tau you can see the larvae can move very well, but then hyperphosphorylated tau in second row, you can see movement deficits in neuromuscular junction, reduction in movement, but then once given agents that reduce tau population, there was suppression of deficit and they can move around quite normally as control even if they express abnormal tau
how can tau abnormailities cause neurodegeneration?
is it tangle or smaller oligomeric species?
-Loss of normal physiological function
(microtubuledestabilisation and cell structure/integrity affected and hyperphosphorylation of tau protein)
-toxic gain of function
So you can imagine that looking at a brain of someone with mild cognitive impairment their temporal lobes haven’t degenerated but they’re dysfunctional (Imaging may show reduced perfusion o2 consumption to those regions of the braindue to less of activity in this region due to the impariement) but at early stages of mild cognitive impairment stages, may depict that the circuit at this time is alive, but there’s disruption in axonal transport and synaptic function due to broken down cytoskeletal integrity.
is it tangle or smaller oligomeric species?
The toxic gain of function means that once a protein is abnormal and starts to do things it wouldn’t normally do.
What is the toxic species?
Is the tangles or a smaller oligomeric species (which are smaller aggregates of misfolded tau proteins that come together).
Which is intermediate. The oligomers are more toxic which contribute to the tangles, and are more mobile, smaller and can spread and cause toxicity all over the place.
The tangles could serve to control the mobile oligomers and fix it in a place rather than spreading everywhere. This is important to think about for therapeutic interventions so if they devise therapies that break these tangles it could have negative implications in the way that the oligomers can be released and spread everywhere again. There’s evidence to suggest form transgenic animals, that once they break down the tangles into oligomers the memory deficits implicated but when they were large accumulated fixed tangles, the memory deficits weren’t present. So, tangles may be a neurones response to prevent toxicity
how does disease spread- traditional and current view
traditional view: Braak staging
current view: cell-cell propagation
Braak staging
A couple going by the name Braak, were neuropathologist studying AD and received brains of AD patients when they die age ranging from 25-90, and they found all of the brains had tauopathies. And its where it is that’s associated with disease, such that they found that most young people never had tauopathy in most regions of brain except one region (Braak stage ½ with no memory deficits). They found that as people go older around 60s, you could have tauopathy spreading in different regions (Braak stage ¾ and develop mild cognitive impairment with memory deficits) and so as you get older there is a spread all over the brain (Braak stage 5/6 that’s profound AD). No one would get a staging of AD unless they’re in Braak stage 5 and 6.
Propagation hypothesis
The tauopathy was spreading via anatomical circuits that were synaptically connected and the chronology of the spread (one happens after the other). Rather than the old view of one area is vulnerable first then another area is vulnerable which isn’t true.
Evidence for this is when a researcher examined brain of this elderly women with Braak stage 5/6, and saw that one part of her bran was completely devoid of the pathology that spread elsewhere to her brain, they found that she had a tumour that was surgically removed 15 years before and so they removed part of the synaptically connected part to the brain region that was devoid of the pathology, suggesting that it spreads through synaptically connected brain regions
How does tau spread?
Mechanism by which the mechanism seems to spread is called seed competence. Such that the misfolded tau can spread through synaptically connected circuits and converts a normal tau protein and to a misfolded protein upon interaction(acquiring same misfold). It can act as a seed, creating more and more misfolded protein which is a toxic effect as its converting unfolded forms of proteins to the same misfold. They are prion-like. Its not a prion as it would be transmitted from person to person which isn’t been found in AD.
If you are going to have cell-cell propagation (pathology spread from cells), the first thing required to demonstrate is that one misfolded protein can act as a seed and convert other proteins to misfold and look like it. And secondly that misfolded protein should spread via synaptically connected circuits
You can see in control no aggregates appearing.
If you inject tau protein, can see appearance of aggregates. Shows that that misfolded tau has ability to act as a seed and presence seed competency.
All the different types of tauopathies had their own specific pathology caused by their specific folds. And when they were injected into brains of animals it presented with the appearance of pathology that was reminiscent of the pathology of the patient.
they have ability to interact with cells and cause to misfold in the same way they were and thus dispkay same fucntional characterisits\
In order for it to be prion like, it need to be a seed, engage in templated conversion and spread
Tau can jump from neurone to neurone between synapses via transporters, exocytosis of vesicles
how can we prove that its tau causing the toxic effect?
transgenic models involve genetically modifying mice to express human tau proteins as a control then another or the same mice (over time) with the mutated version of human tau known to cause disease. This approach allows researchers to study the progression of tau pathology and its effects on brain function in a controlled, living organism that mimics human disease.
