Alzeimers And Taupathies Flashcards
What is Alzheimer’s?
Decline in Cognitive processes
Leading cause of dementia
Caused by plaques and tangles
1/16 - 60+ will have it
What is dementia
When memory loss interferes with day to day life
Eg forgetting where they parked, will never find them
Cause by chronic and acute diseases
Parts of brain mostly impacted by AD
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
Temporal lobe
Involved in processing information there and then
Eg eat a meal and forget they’ve eaten
Parietal lobe
Processes sensory info and spatial awareness
Why are people given the diagnosis “probable AD”
Cannot be definitively diagnosed until brain is searched for plaques and tangles after death
Similarities between AD and other l neurodegenerative diseases
All have tauaphagies
All dementias
Differences between AD and other related diseases
Most others don’t have amyloid pathology
Different regional vulnerabilities
Clinical symptoms of frontaltemporal dementia
Innapropriate actions - disinhibition
Poor judgement
Apathy
Eg picks disease
Why are those with AD given cholinesterase inhibitors
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)
What are the hallmarks of AD
Abnormal proteins:
Neuritic plaques - amyloid
Neurofibrillary Tangles - tau
Neurofibrillary tangles
Intracellular lesion
Made up of Microtubule associated protein called tau
Protective measures of AD
Mediterranean diet - gut brain axis, Microbiome
Exercise - increases blood flow to brain and decreased risk of diabetes (associated with AD)
Coffee - antioxidants
Why aren’t there effective treatments for AD?
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)
Why is tau/tangle pathology implicated in AD
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
Main cause of neurodegenerative diseases
Abnormal tau
How is tau abnormal in AD and other tauopathies?
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)
Evidence tau is phosphorylated
Western blot
AD - 6 bands squished into 3, retarded gel motility (add phosphotases and pattern returned)
Control - six bands spaced out
Do the tau 3 and 4 repeats cause different protein folding to eachother
Yes
3 cause picks disease
4 cause PSP
Do different regions of the brain have vulnerabilities to different confirmers
Currently being researched
Potential theory
Mechanisms tau abnormalities cause neuronal dysfunction
Loss of normal physiological function
Gain of toxic function
Taus normal function
Microtubule stabilising protein to keep up efficient axonal transport of neurotransmitters
What happens when tau becomes abnormal
Ability to bind to Microtubules impaired
Microtubule cytoskeleton collapses
Cytoskeleton disrupted so compromised axonal transport
Testing tau-MT hypothesis
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
How can we counter abnormal tau mediated neuronal dysfunction?
[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
How can we tell the axon was sick and not dead
Electrical response
Axonal transport
Can NAP rescue P-tau phenotypes?
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
Why did the NAP drug not work in advanced AD
Neurone dead
Switch from loss of function to gain of function
How can tau abnormalities cause neurodegeneration
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
Proteinopathies
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)
Prion proteins
Proteins that can covert other proteins to look like themselves and so infect other proteins
How does disease spread? Traditional view Braak staging
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
How does disease spread? Current view cell to cell propagation
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
Seed (in tau pathology)
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
Can tau pathology spread from mouse to mouse like prion pathology
Yes
Injected one mouse. Then take that mouse gray matter inject into next and so on
What is important about knowing the type of tau pathology and confirmer
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
Similarities of confirmers of tau
All lead to aggregation of protein
Have ability to engage in template seeding
All effect axonal transport
All abnormally phosphorylated
Differences of tau confirmers
Different sites are phosphorylated and different times (potentially)
Differential conversion ability (potentially)
What therapies could be designed
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?)
