Neurodegeneration Flashcards
Define Prion diseases. How is it acquired?
A series of diseases with common molecular pathology
Transmissible factor
No DNA or RNA involved
Prion (pr*_oteinaceous _*i*_nfectious _*only)
Also called spongiform encephalopathy
What are the types of Prion diseases?
Humans
- Creutzfeldt-Jakob disease - most common
- Gerstmann-Straüssler-Sheinker syndrome
- Kuru
- Fatal familial insomnia
H&E stain
Spongiform change
Prion protein deposits
Describe the development of the prion protein.
- The normal PrPSc protein can unfold and refold into a beta-pleated sheet form which is much more susceptible to aggregation
- Once a little bit of this forms, it can propagate
- This leads to a lot of insoluble protein accumulating in the parenchyma of the brain
What is the new Variant CJD (vCJD)? Who gets affected? What is it associated with?
Bovine spongiform encephalopathy - BSE
What is the neuropathology 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)
- Shrinkage of brain
- Hippocampus (inf. horn of lat. ventricles often affected) → loss of short-term memory
- Neurofibrillary tangles (tau)
Right: large ventricles and cerebral atrophy - AD
Senile plaques in the brain
Cerebral amyloid angiopathy
What is the APP structure?
What is APP processing? Which pathway is more common?
Non-amyloidogenic pathway
What do amyloid plaques do?
Tau immunostaining - deposition
- This is a microtubule-associated protein (used for maintaining stability of the cytoskeleton)
- When it becomes hyperphosphorylated it starts causing problems
- Accumulates inside the cell and eventually it will cause cell death
- Presence and spread of tau throughout the brain is quite stereotypical and matches up quite closely with the clinical symptoms seen in the patient Braak staging (clinical symptoms, location and amount of Tau)
How do we stage Alzheimer’s disease
-
Tau progression (Braak staging) / symptoms [S] appear at stage 3 or 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)
Mid brain - lost almost all pigment in substantia nigra
What is the progression of Parkinson’s?
- Characterised by the presence of Lewy bodies = cells with a-synuclein (LBD = Lewy Body Dementia)
- Dopaminergic cells produce neuromelanin → colours the substantia nigra (SN)
- Parkinson’s disease = death of dopaminergic cells of SN → coloration of SN lost
- Cells from the SN project to the basal ganglia (caudate and putamen)
- Basal ganglia are very important in the initiation of movement
- S/S = bradykinesia, rigidity, pill-rolling tremor
Smooth hyaline inclusions - Lewy body
What is the diagnostic gold standard for Parkisons?
- Lewy bodies are intracellular accumulations of a-synuclein
- Parkinson’s disease = a proteinopathy developed from abhorrent metabolism of a-synuclein – mutations in a-synucleingene → PD
- a-synuclein immunostaining = diagnostic gold standard
Describe the staging of Parkisnons.
-
Braak PD stages:
- Based on the distribution of a-synuclein pathology throughout the brain
- Bottom-up spread (originate in the brainstem) → from the medulla, up the pons and the midbrain (so nigral pathology is only stage III) → moves into the basal forebrain and the cortices
What is the significance of peripheral ganglia?
-
NOTE: pathology is also seen in peripheral ganglia, in the gut and in the nose (i.e. anosmia is an early sign of PD)
- Sleep disorders are considered to be a prodrome for Parkinson’s disease
There may be an environmental factor
What are the causes of Parkinsonism?
- Idiopathic Parkinson’s disease•Drug-induced Parkinsonism
- Multiple system atrophy - may present as a cerebellar or Parkinsonism type problem
- Progressive supranuclear palsy
- Corticobasal degeneration
- Vascular pseudoparkinsonism
- Alzheimer’s changes
- Fronto-temporal neurodegenerative disorders
- 20 other disorders
What is the pathology of multiple system atrophy?
- a-synucleinopathy → however, it targets glial cells
- It tends to affect the cerebellum and the patients are more likely to present with falls
What are the tau immunostaining diseases?
- Progressive Supranuclear Palsy / PSP
- Corticobasal Degeneration / CBD
- Pick’s disease
MSA
Corticobasal degeneration
Progressive supranuclear palsy
What is Pick’s disease?
Fronto-temporal atrophy
Marked gliosis and neuronal loss
Balloon neurons
Tau positive Pick bodies
Tau positive pick bodies in the hippocampus
Describe the tau structure ?
Single gene on 17q21
16 exons
Alternative splicing gives rise to 6 isoformsv3R or 4R-tau (microtubule-binding domains)
Two further inserts with unknown functionvShortest form (3R/0N) foetal
Describe the different isoforms of tau?
What is the significance of the types of tau?
-
AD = all 6 types of Tau (4R and 3R)
- When Alzheimer’s disease tau is put through a Western blot it will form 3 dense bands – if this is dephosphorylated, it shows that all 6 types of tau are involved (4R and 3R components)
-
CBD/PSP = 4R tauopathy
- CBD and PSP → 2 dense bands → when dephosphorylated are made up of only the 4R bands
- Pick’s disease = 3R-tauopathy
Describe front-temporal lobar dementias. What are the genetic bases? What mutations is it associated with? What is it also associated with?
- There are many forms of fronto-temporal dementia with different genetic bases:
- FTLD-tau (Pick’s disease, PSP, CBD)
- Tau-negative FTLDs (i.e. FTLD-U (ubiquitinated) from mutations in progranulin)
- Fronto-temporal dementia associated with progranulin mutations → tendency for the atrophy to be unilateral
- Problems with TDP-43 (trafficking protein) thought to be the basis for some types of FTLD (associated with MND)
- TDP-43 = TAR DNA Binding Protein 43
- Other associations:
- FUS pathology
- C9ORF72 mutations
