HISTO: Neurodegeneration Flashcards
What is the transmissible factor in prion disease? Can it be cleared?
There is a transmissible factor but there is no DNA or RNA involved. “Prion” = Proteinaceous Infections Only
The prion protein is transmitted and changes the host protein into the pathological form but cannot be metabolised and accumulates
List 3 examples of prion disease in humans.
- Creutzfeldt-Jakob disease (CJD)
- Gerstmann-Straussler-Sheinker syndrome
- Kuru (“to shake” – endemic to Papua New Guinea)
- Fatal familial insomnia
What is the histology in prion disease?
HEE stain - spongiform changes
What is the pathophysiology of prions?
- Normally a n alpha helical format which is loosely folded but …
- … the normal PrPSc protein can unfold and refold into a beta-pleated sheet
- This beta pleated sheet is more susceptible to aggregation
- In some people this can lead to PrPScseed
- This can propagate and accummulate in the parenchyma of the brain
What is new variant vCJD linked to? What are the clinical features?
Linked to BSE (Mad Cow Disease)
- Clinical features:
- Patients <45yo
- Cerebellar ataxia
- Dementia
- Longer duration than CJD
- Diagnosed at autopsy
What is the neuropathologcal components of AD?
- Extracellular/senile plaques (amyloid-beta)
- Neurofibrillary tangles (Tau)
- Disrupts cytoskeleton of neurones
- Cerebral amyloid angiopathy (CAA)
- Deposits of proteins in the blood vessel walls
- Impairs vascular function
- Neuronal loss (cerebral atrophy)
Where does neuronal loss commonly occur in AD? What is the clinical consequence?
Severe atrophy of the hippocampus (inf. horn of lat. ventricles often affected) –> loss of short-term memory
What is shown?
Senile plaques
Lump of protein –> halo –> more diffuse protein (we think that this is protein that has been extravasated from cells)
What is shown?
Cerebral amyloid angiopathy
- Deposits of proteins in the blood vessel walls
- Impairs vascular function
Where does the Abeta sequence sit in the APP?
Membrane
APP structure
How is A-beta formed?
- Ab is formed by cleavage of APP at a transmembrane site
- APP can be processed in TWO ways; one is amyloidogenic, the other is non-amyloidogenic:
- Non-amyloidogenic - Absequence directly cleaved in two
- Amyloidogenic - Amino terminus of Ab cleaved –> amyloidogenic –> too much Ab –> so Ab thrown out of cell and accumulates –> Ab forms monomers, to oligomers (dimers), to protofibrils and then fibrils (polymers)
Where is A-beta most toxic?
Intracellularly
Extracellularly its plaques probably do not cause direct problems
What is shown?
Tau
What is the function of Tau normally?
Tau protein is a soluble protein present in axons
Tau important for assembly and stability of microtubules
What is the pathophysiology of Tau?
- Hyperphosphorylated tau is insoluble –> self-aggregates
- The self-aggregates form neurofibrillary tangles (neurotoxic)
- The tangles result ultimately in microtubule instability and neurotoxic damage to neurones
What is the normal physiology of amyloid?
- APP cleaved by a-secretase
- sAPPa released and the C83 fragment remains
- C83 is then digested by g-secretase
- Products are then removed
What is the pathophysiology of amyloid/APP in AD?
- APP cleaved by b-secretase
- sAPPb released and the C99 fragment remains
- C99 is digested by g-secretase releasing b-amyloid (Ab) protein
- Ab protein forms the toxic aggregates
What are CNS macrophages called?
Microglial cells
What staging is used for measuring Tau progression?
Braak staging - symptoms [S] usually appear at stage 3/4
- Stage I = trans-entorhinal region
- Stage II = entorhinal region (interfaces neocortex and hippocampus)
- Stage III [S] = temporo-occipital gyrus (see the immunostaining by eye)
- Stage IV [S] = temporal cortex
- Stage V = peri-striatal cortex (cortex around the primary visual cortex)
- Stage VI = striatal cortex (occipital lobe)
How does Tau presence and spread correlate with symptoms?
- Presence and spread of tau throughout the brain matches up closely with the clinical symptoms seen in the patient
- Braak staging - uses clinical symptoms, location and amount of Tau
Menti: Tau immunostaining in the peristriate but not the striate cortex is consistent with which Braak staging ?
V
What is PD characterised by the presence of?
- Characterised by the presence of Lewy bodies = cells with a-synuclein (LBD = Lewy Body Dementia)
What are Lewy bodies?
Intracellular accumulations of alpha-synuclein
What symptoms occur as a result of degeneration of cells projecting from the SN to the basal ganglia (caudate and putamen)?
- Basal ganglia are very important in the initiation of movement
- S/S = bradykinesia, rigidity, pill-rolling tremor
What is the diagnosic gold standard in histology in PD?
a-synuclein immunostaining
Which neurons die in PD? Why does the SN become discoloured?
Dopaminergic neurons are lost - usually produce neuromelanin
Their loss causes loss of colour of the substantia niagra
What is the proteinopathy in PD?
Proteinopathy developed from abhorrent metabolism of a-synuclein – mutations in a-synuclein gene –> PD
What is the Braak staging of PD based on?
- Based on the distribution of** **a-synucleinpathology throughout the brain
What is the sequence of Lewy body spread (and according to Braak staging of PD)? If niagral pathology is seen what is the stage?
Bottom-up spread (Lewy bodies originate in the brainstem) –> from the medulla, up the pons and the midbrain
Nigral pathology is only stage III –> moves into the basal forebrain and the cortices
What % of neurons need to be lost for symptoms to occur?
- About 60-70% of nigral neurones need to be lost
In PD, apart from the brain, where else is neuropathology seen?
Peripheral ganglia of the:
- Gut
- Nose - anosmia is an early sign of PD
Sleep disorders are also an early sign of PD
What % of PD aetiology is genetic?
<5%
Rest is thought to be environmental
Summarise two environmental aetiology theories for PD.
If an environmental agent is implicated, there are two potential access points:
- Retrograde from the gut to the medulla via the vagus nerve
- Through the nose
What are some differentials for PD?
(conditions where Parkinsonism is observed)
- Idiopathic Parkinson’s disease
- Drug-induced Parkinsonism
- Progressive supranuclear palsy
- Corticobasal degeneration
- Vascular pseudoparkinsonism
- Alzheimer’s changes
- Fronto-temporal neurodegenerative disorders
Excluding PD which other disorder, often presenting with parkinsonism is associated with alpha synuclein pathology?
MSA - multiple system atrophy
In contrast to PD, what cells does multiple system atrophy affect?
It is also an alpha-synucleinopathy but targetting the gllial cells
What symptoms does MSA ususally present with and why?
Falls as pathology affects the cerebellum
List 3 Tau immunostaining diseases.
- Progressive supranuclear palsy - PSP
- Corticobasal degeneration - CBD
- Pick’s disease
How does Pick’s disease present?
Tend to present with frontal lobe pathology (e.g. dysexecutive syndrome)
What is the histology of Pick’s disease?
- Fronto-temporal atrophy
- Marked gliosis and neuronal loss
- Balloon neurons
- Tau-positive Pick bodies
What is the inheritance pattern of Tau mutations? How many syndromed result from these? What are these called and why?
- Autosomal dominant
- 17 syndromes
- FTDP-17 - fronto-temporal dementia phenotypes 17 - called this as it presents with a fronto-temporal dementia phenotype which is more like that of PD than AD (Alzheimer’s)
What types of mutations cause tau pathology as seen in FTDP-17?
Missense and splicing mutations
>20 pathogenic mutations have been identified
There is a single gene for Tau on 17q21 with 16 exons which can be alternatively spliced. If they are alternatively spliced, how many isoforms of tau form?
6 isoforms
Tau isoforms - significance of these is that they can be visualised on Western Blot
AD is seen in the first column at the bottom alongside differentials for AD
What are the two forms of tau? What are the two forms which are the longest and shortest?
There are either 3R or 4R forms of tau - depending on the number of microtubule-binding domains that exist in the brain
There are then TWO further subsets with unknown functions:
- The longest form is 4R/2N
- The smallest form is 3R/0N
What is the significance of the types of tau in the 3 tau immunostaining diseases and AD?
CBD/PSP = 4R tauopathy
- 2 dense bands formed + when dephosphorylated are made up of only the 4R bands
Pick’s disease = 3R-tauopathy
- 2 dense bands formed + when dephosphorylated are made up of only the 3R bands
AD = all 6 types of Tau (4R and 3R)
- In AD tau on Western Blot will form 3 dense bands – if this is dephosphorylated, it shows that all 6 types of tau are involved (4R and 3R components)
Menti: Which of the following proteins is not associated with forms of frontotemporal dementia?
- APP
- Tau
- TDP
- FUS
APP
Are fronto-temporal lobar dementia ubiquinated (FTLD-U) tau positive or negative?
NEGATIVE
What mutations is FTLD-U associated with?
Progranulin mutations - these cause tendency for atrophy to be unilateral
Which protein may be defective in FTLD-U? What is its significance in other conditions?
TDP-43 (TAR DNA binding protein 43) - this is a trafficking protein
May be the basis for some types of FTLD and is also associated with MND
What is Dementia Lacking Distinctive Histology (DLDH) aka?
AKA ubiquitin-negative FTLD
