Alzeimers And Taupathies

Question 1

What is Alzheimer’s?

Answer 1

Decline in Cognitive processes
Leading cause of dementia
Caused by plaques and tangles
1/16 - 60+ will have it

Question 2

What is dementia

Answer 2

When memory loss interferes with day to day life
Eg forgetting where they parked, will never find them

Cause by chronic and acute diseases

Question 3

Parts of brain mostly impacted by AD

Answer 3

Starts on in temporal cortex (cell death) - short term memory loss
Parietal cortex - processes sensory and spatial info
Hippocampus (entorhinal cortex) - impairment of recent memory functions and attention
Cortex (basal nucleus of meynart) - failure of language skills, disorientation, impaired judgement, personality changes

Question 4

Temporal lobe

Answer 4

Involved in processing information there and then
Eg eat a meal and forget they’ve eaten

Question 5

Parietal lobe

Answer 5

Processes sensory info and spatial awareness

Question 6

Why are people given the diagnosis “probable AD”

Answer 6

Cannot be definitively diagnosed until brain is searched for plaques and tangles after death

Question 7

Similarities between AD and other l neurodegenerative diseases

Answer 7

All have tauaphagies
All dementias

Question 8

Differences between AD and other related diseases

Answer 8

Most others don’t have amyloid pathology
Different regional vulnerabilities

Question 9

Clinical symptoms of frontaltemporal dementia

Answer 9

Innapropriate actions - disinhibition
Poor judgement
Apathy
Eg picks disease

Question 10

Why are those with AD given cholinesterase inhibitors

Answer 10

Basal nucleus of meynert - cholinergic symptom impacted
Choliesterase inhibitors boost this circuit

Symptoms: attention, arousal, cognition (impaired judgement, personality changes, failure of language skills, disorientation)

Question 11

What are the hallmarks of AD

Answer 11

Abnormal proteins:
Neuritic plaques - amyloid
Neurofibrillary Tangles - tau

Question 12

Neurofibrillary tangles

Answer 12

Intracellular lesion
Made up of Microtubule associated protein called tau

Question 13

Protective measures of AD

Answer 13

Mediterranean diet - gut brain axis, Microbiome
Exercise - increases blood flow to brain and decreased risk of diabetes (associated with AD)
Coffee - antioxidants

Question 14

Why aren’t there effective treatments for AD?

Answer 14

Too late by the time symptoms develop (80% degeneration before symptoms appear and can’t bring circuits back)

Effective biomarkers are needed to pick up the disease through screenings before symptoms occur (remaining circuits compensate for circuits that are lost)

Question 15

Why is tau/tangle pathology implicated in AD

Answer 15

Tau alone sufficient to cause degeneration without amyloid pathology (other things can trigger tau abnormality)

Abnormal Amyloid genes believed to trigger the formation abnormal tau causing degeneration

Question 16

Main cause of neurodegenerative diseases

Answer 16

Abnormal tau

Question 17

How is tau abnormal in AD and other tauopathies?

Answer 17

Mutated in FTDP 17
Abnormally expressed in FTD and AD (mutation in splice region, more 3 or 4 repeats in Microtubule binding tau causing tauapathy)
Forms filaments and causing aggregates in all (folding different in the different diseases)
Hyperphosphorylated in all (abnormal regulation, 100% sites phosphorylated)

Question 18

Evidence tau is phosphorylated

Answer 18

Western blot
AD - 6 bands squished into 3, retarded gel motility (add phosphotases and pattern returned)
Control - six bands spaced out

Question 19

Do the tau 3 and 4 repeats cause different protein folding to eachother

Answer 19

Yes
3 cause picks disease
4 cause PSP

Question 20

Do different regions of the brain have vulnerabilities to different confirmers

Answer 20

Currently being researched
Potential theory

Question 21

Mechanisms tau abnormalities cause neuronal dysfunction

Answer 21

Loss of normal physiological function

Gain of toxic function

Question 22

Taus normal function

Answer 22

Microtubule stabilising protein to keep up efficient axonal transport of neurotransmitters

Question 23

What happens when tau becomes abnormal

Answer 23

Ability to bind to Microtubules impaired
Microtubule cytoskeleton collapses
Cytoskeleton disrupted so compromised axonal transport

Question 24

Testing tau-MT hypothesis

Answer 24

Transgenic fruit flies (transparent)
GFP tagged neuropeptide y
Introduce different taus
Abnormal tau introduced, reduction in binding of tau to Microtubule
Drug that reduces phosphorylation reduces this effect
Electron Microscope - see breakdown of cytoskeleton
GFP - look at axons, pile up in axons, NT won’t be released in motor neurones, neuromuscular junction impaired, impaired movement

Question 25

How can we counter abnormal tau mediated neuronal dysfunction?

Answer 25

[glycogen] Kinase inhibitors (went into clinical trials but failed due to side effects because very promiscuous)

Increase phosphatase activity (difficult but hook to tau)

Microtubule stabilising agents

Question 26

How can we tell the axon was sick and not dead

Answer 26

Electrical response
Axonal transport

Question 27

Can NAP rescue P-tau phenotypes?

Answer 27

Yes
Same tau and phosphorylation
Axon stabilised so axon alive and reverted when given drug
Less aggregates
Less synaptic deficits
Behaviours normalised

BUT failed clinical trial - worked in those with mild cognitive impairment and not in advanced AD

Question 28

Why did the NAP drug not work in advanced AD

Answer 28

Neurone dead
Switch from loss of function to gain of function

Question 29

How can tau abnormalities cause neurodegeneration

Answer 29

Toxic gain of function:
Expression of mutant tau in animal models
Oxidative stress, apoptosis, necrosis or so ace occupying lesions

Prion like pathology of tau

Question 30

Proteinopathies

Answer 30

Diseases that are caused by abnormal protein
Protein aggregates (misfolds so aggregate prone - can aggregate and convert other normal proteins to abnormal: prion like conversion or templates seeding)

Question 31

Prion proteins

Answer 31

Proteins that can covert other proteins to look like themselves and so infect other proteins

Question 32

How does disease spread? Traditional view Braak staging

Answer 32

Early 20s/30s people had tau pathology in entorhinal cortex. If it leaves entorhinal region and spreads around neuro anatomically linked regions than classed as pathology in older people.
Disease spread reflects clinical symptoms

But is there differential vulnerability and did it spread or already there?

Disconnection prevents region getting taupothology through circuit

Question 33

How does disease spread? Current view cell to cell propagation

Answer 33

Vivo demonstration: transgenic mice normal tau and misfolded tau
Inject abnormal tau into normal tau brain to see if it it converts it
Result: Lots of aggregates and spread to neuro autonomically linked regions

A seed is required for spread of tau pathology From aggregate prone tau to non aggregate prone tau

Tau aggregates in prion like manner

Question 34

Seed (in tau pathology)

Answer 34

Requires tau
Can be induced by tau filaments and oligomers
Acts in a prion like templates fashion (non random, specific pattern way of misfolded and conversion) different in the different neurodegenerative diseases
Tested by injecting different gray matter with different neurodegenerative diseases into regular tau mice

Question 35

Can tau pathology spread from mouse to mouse like prion pathology

Answer 35

Yes
Injected one mouse. Then take that mouse gray matter inject into next and so on

Question 36

What is important about knowing the type of tau pathology and confirmer

Answer 36

Make confirmer specific treatments
May give different symptoms based on where the confirmer is more potent due to region of brain impacted
Can try to diagnose more accurately and sooner so better treatment

Question 37

Similarities of confirmers of tau

Answer 37

All lead to aggregation of protein
Have ability to engage in template seeding
All effect axonal transport
All abnormally phosphorylated

Question 38

Differences of tau confirmers

Answer 38

Different sites are phosphorylated and different times (potentially)
Differential conversion ability (potentially)

Question 39

What therapies could be designed

Answer 39

Block receptors that are permissive to the spread to prevent spread of disease to other regions of brains
Bio marker work to try diagnose/prevent earlier
Prevent conversion
Immunotherapy - get rid of seeds and aggregates (meningitis possibility? May not be worth risk. How do we know it won’t impact healthy tau?)