Alzheimer's disease Flashcards
who first described alzheimer’s disease?
When?
First described in 1906 but Alois Alzheimers
describe the discovery of alzheimers
Auguste De, a middle aged house wife was brought to Alois Alzheimer because she was struggling with her day to day activities
when she died, Alois observed her brain was more than a third shrunken than a typical person of that age
he drew two major structures that he saw - neuronal plaques adn tangles
which region of the brain is primarily affected by alzheimers disease?
temporal lobe
clinical symptoms are a reflection of…
a reflection of the circuitry that is effected in the brain
when is a definitive diagnosis of alzheimers given?
when the patient dies and the plaques and tangles are seen in their brain
When the clinical symptoms appear as alzheimers then they are given the diagnosis of probable alzheimers
what is dementia?
Impairment in cognitive faculties that interferes with you day to day activities
what is unique about alzheimers disease in terms of tauopathies?
it has plaques and tangles
all dementias are tauopathies but other tauopathies dont have amyloid pathology and start in different regions of the brain
what are the similarities and differences between different types of (tau) dementia?
similarites - all are tauopathies
differences - alzheimers involves amyloid pathology, different spatial pathology (starting in different brain regions)
if the hippocampus-entorhinal cortex is effected what symptoms will be exhibited
impairment of recent memory
functions and attention
if the cortex-basal nucleus of meynert is affected what symptoms will be exhibited?
(4) (basal forebrain)
failure of language skills
disorientation
impaired judgment
personality changes
what do cholinesterase inhibitors do?
boost the circutry - so that the remaining neurons continues to be as functional as possible
basal nucleus of Meynert is a cholinergic system
Deficits in functions in the nucleus basalis of Meynert are observed in neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. Because of these changes, the cholinergic system was implicated in playing a role in the cognitive symptoms observed in Alzheimer’s disease
what are neural plaques?
extracellular lesions made of amyloid Aβ
what are neurofibrillary tangles?
– intracellular lesion, made of a microtubular protein tau (involved in transport)
what is tau?
most abundant microtubular associated protein in the neurons
stabilises microtubules in neuronal axons
give two reasons why we dont have effective alzheimers treatments
the neurodegeneration has progressed too far before the symptoms show up - too much dmaage has been done by the time there are clinical symptoms
there are no effective biomarkers - we cant pick up the presence of the abnormal protein before it starts to cause damage
what percentage of alzheimers is familial?
15%
give two things that are thought to reduce the risk of alheimers?
meditarranean diet - throught to be protective becase it has many antioxidants
excerise - it increase blood flow to the brain and reduces other comorbitities like cardiovascular disease and type 2 diabetes
mutations in tau:
DO NOT cause….
but
DO cause….
DO NOT cause alzheimers
DO cause fronto-temporal dementia
abnormal tau leads to formation of…
formation of tangles which causes neurodegeneration and clinical symptoms
why was there debate in the cause of alzheimers and what settled it?
APP gene create amyloid precursor protein, several mutations were identified to lead to alzheimers disease, but there were non in the tau gene, it was thought to be a downstream effect
Mutations in in tau causse frontotemporal dementia (very similar to alzheimers, different region where the pathology starts), only have tau and still have degeneration
This made people change their mind, because tau was found to cause degeneration in other diseases but amyloid wasn’t – telling us abnormalities in tau are sufficient to cause degeneration
Amyloid is upstream of tau but it is when tau begins to become abnormal degeneration occurs
when is Tau never mutated?
in alzheimers
how is tau abnormal in alzheimers and other tauopathies?
tau is mutated
tau is hyperphosphorylated
tau is abnormally expressed
tau forms filaments
what two tau abnormalities occurs in all tauopathies?
Tau is hyperphosphorylated and Tau forms filaments in all tauopathies
when a disease is caused by an abnormal protein what two things lead to the clinical affects?
1) Loss of normal physiological function
2) Gain of toxic function
what percentage of tau protein in the body is phosphorylated?
in the adult body
5%
what percentage of tau protein in the body is phosphorylated?
in fetal development
20%
what percentage of tau protein in the body is phosphorylated?
in alzheimers
100%
how many phosphorylation sites are there on tau
75
how may tau be abnormally expressed?
normally 3 repeat tau and 4 repeat tau are expressed in an equal ratio
in alzheimers the ratio is wrong due to problems in regulatory eleements causing alternative splicing that results in excessive amounts of 3 repeat tau OR 4 repeat tau
the exons in the tau gene can be spliced differentially to include exons _ and/or _ and 10? the splicing occurs differently in disease causing abnormal expression of either 3 or 4 repeat forms
hwo many isoforms of tau are there
6
3 have 3 binding domains (3 repeat tau)
3 have 4 binding domains (4 repeat tau)
how was it discovered that tau in alzheimers was highly phosphorylated?
When isolated on a gel, tau has six different isoforms in normal, in alzheimers the bands are squished into three bands, retarded (heavier) gel motility, telling us that it is highly phosphorylated. – incubate with phosphatases the banding pattern reverted back to the control, or stain with phosphospecific antibodies.
why is formation of tau filaments damaging to a neuron?
it causes aggregation of protein that accumulates meaning that there is no space for the neurons to carry out its normal cellular function
what is different between the molecular tau in different tauopathies?
When tau misfolds and causes tangle – resulting in different types of conforma
Some taupothies look different than others, they are all aggregates of tau but the way tau is folded is different
Relationship unknown – potentially the phosphorylation pattern, or the ratio of 3 and 4 repeats Pics disease have excessive amount of 3 repeat PSP have excessive 4 repeats Different conformas in diseases – do certain regions of the brain have different susceptibilities to different conformas
what is the normal physiological function of tau?
Inside axon there is a microtubular cytoskeleton
Microtubules are unstable, they breakdown all the time, tau is a stabilising protein that keeps them together
Tau important for enabling an efficient transport system to be created
what was the hypothesis set out by Sir lovestone?
whenever tau is abnormal, the first thing that happens is their ability to bind to microtubules fails, and the microtubule collapses, so no track for axonal transport to occur so that they can’t connect with other neurons
what evidence is there for sir lovestones theory
- there is a dramatic disruption of tau binding to microtubules when its phosphorylation - phosphatases reduces this effect.
- Microtubule cytoskeleton breaks down - when tau is highly phosphorylated you can see very few MT structures under electron microcope
- axonal transport disrupted - we see pile ups of vesicles in the axons
- this means neurotransmitter wont be released - we see that the neuromusclar junction is shrinking and dying confriming this
- Behavioural defects are seen (maggor races or righting assays)
- if you remove phosphoyrlatin this all returns to normal
- other proteins always wont reach the synapse so we see locomotor impairments or aparlsysi
what possible mechanisms are there for the toxic gain of function of tau?
expression of mutant or phospho-mimicking tau in animal models causes neurodegeneration
mechanism unclear but various suggestions including oxidative stress, apoptosis, necrosis or simple space occupying lesion
How can we counter abnormal tau mediated neuronal dysfunction?
(foundation -2)
1) reduce tau phosphorylation: kinase inhibitors
2) microtubule stabilising agents
what medication, used for a psychiatric disorder, was tried as a treatment for alzhiemers?
Lithium chloride: it was noticed that bipolar patients being treated with lithium chloride, had a much lower appearance of alzheimers disease thought to be due to the glycogen synthesis kinase activity of lithium chloride
why did the clinical trials of lithium chlorides (as an alzhiemers treatment) fail?
Thought to be a potential treatment for alzhiemers however when they reached clinical trials they did not work – there were too many side effects which caused reduced compliance (patients didn’t want to take it because they got too sick), meaning that they couldnt tell if the results were due to the drug or not.
These side effects were potentially due to glycogen synthesis involvement that is important for all neurons – not selective for neuronal kinase
give four peices of evidence that suggest NAP can rescue p-tau phenotypes?
- Even in the presence of highly phosphorylated tau, the axons look far more normal when NAP is applied
- It also reverted axonal transport – pile ups virtually disappear
- Neuromuscular junction also rescued
- When applying the drug to p-tau maggots it was able to almost revert their movement back to normal
what is NAP?
a neuroprotective drug candidate in clinical trials, stimulates microtubule assembly in the living cell
give an example of a microtubule stabilising drug
NAP
why did NAP fail in trials?
it worked on those with mild cognitive function however in patients with advanced alzhiemers it did not
Due to too much p-tau build up resulting in toxic gain of functions and formation of tangles. Also those that had the disease for years also had neuronal death which the drugs clearly can have no effect on
how could tau abnormalities cause neurodegeneration by toxic gain of function?
expression of mutant or phospho-mimicking tau in animal models causes neurodegeneration
mechanism unclear but various suggestions including oxidative stress, apoptosis, necrosis or simple space occupying lesion
and spread of pathology
to become aggregate prone means two things…
1) able to aggregate
2) able to convert normal protein to abnormal protein (like itself)
= prion like conversion/ template seeding
what are proteinopathies?
conditions where normal proteins have started to aggregate
misfolds -> becomes aggregate prone
why is it called template seeding?
Template seeding because a seed is able to create more of itself – the protein will have identical abnormalities to the seed its converted by
why is it knwon as prion-like conversion?
Named prion like conversion due to its similarity to the ability of prion to convert other prions in prion disease – infectious spread
describe the experiment that was the basis of Braak staging?
900 subjects ranging in age from 25-90 years were analysed
Disease spread reflect clinical symptoms
There is stereotypical spread of pathology across connected brain regions
It was observed that young people 20s-30s had tau pathology in the entorhinal cortex and over time 60s-70s this spreads out of the temporal cortex – and only then do the symptoms of Alzheimers appear
