Patterns and overlaps Flashcards
What is Neurodegeneration ?
- Selective loss of neurones leading to atrophy
- Gliosis- brains form of scarring
- Progressive
- usually some regional or system specificity- one bit suffers worse than others
- Usually age related
- Multiple pathologies
Alzheimers pathology
Gyri wider and sulci narrow
- everything seems to shrink
HD pathology
- Lateral ventricle bigger
In Basal ganglia – head of caudate convex to concave
MN
motor neurone loss from anterior horns
Effects system of the musculature and motor functions
Loss of neurons
Astro gliosis – HD
- Not essential for communication
- Provide trophic support
- GFAP marker used to mark astrocytes
- Huntingtons – more astrocytes- bigger and prliferative
- Can modify behavior of disease can be benefical or actively toxic and encourage neurons to die
- Alter disease phenotype
What is associated with a cognitive impairment?
A Reduced Astrocyte Response to β-Amyloid Plaques in the Ageing Brain Associates with Cognitive Impairment.
Astrocytic plaques
Marked astrocytic reaction to beta amyloid plaques correlated with dementia phenotype
MN/ ALS :
Research
- Sod1 most common mutated genes
- selectively express mutant or wt sod1 in astrocytes you can alter disease phenotype you see
- mouse with mutant MN and then introduces wt astrocytes can reduce phenotype/progression
Microglia
- Immune cells of the brain
- Monocytes related to macrophages
- Most common reaction to any insult in brain is microglial
- Sensitive but non specific indicator of disease – marker CD68
- No microglia – normal
- Resident immune cell of the CNS
- Mononuclear phagocytes of myeloid origin
- ~1-15% of cells in adult human CNS
- Regional variation
- Enter brain in early development
- Microglial marker expression correlates with Disease phenotype
- Other pathological markers of neurodegenerative disease
- Microglial activation can influence astrocytic neuro toxicity/protection (doi:10.1038/nature21029)
- Don’t rest – constantly monitoring env looking for trouble- if encounter something processes become fatter and shorted and become a round blob shape – Repsond to injury
- Like the army – lots of things they can do – destructive and constructive roles – toxic and kill things or trophic and provide supportive feeding role to existing neurons – dependent on disease phenotype
M0
resting
M1
Killer/Classic activation
M2
Supportive and constructive wound healing
Microgliosis
common feature of neurodegenerative disease and can modulate observed disease phenotype
-Ventral horn – MN
Motor axons – between microglia
common theme of neurodegenerative diseases
Deposits of protein
– protein deposits begin in specific areas then continue to spread in a step wise place specific manner
BRAK staging
stage of disease related to spread of tau
Protein deposits:
- Hypophosphorylate Tau protein
- Beta amyloid plaques
- Lewi bodies – dementia
- Parkinsons- Lewi bodies hard protein inclusions – loss of neurons in SN – protein is alpha synuclein
- Huntington’s – characterized by repeat CAG glutamine get poly glutamine – immunohistochemistry
- MN- protein deposited TDP-43 – shuttles between nucleus and cytoplasm – important in RNA processing neurons die
- All these proteins can be ubiquitin tagged
Ubiquitination
Large number of diseases characterised by ubiquitin aggregates
What is another form of classification ?
Classify neurodegenerative diseases by what protein is aberrantly deposited and where?
Inclusions – common in many diseases
TDP43 and Tau
Implicated in a lot of diseases
What is the cognitive phenotype related to ??
Area affected
- neurodegenerative disease can present with motor/cognitive or both
Conditions of overlap
Neurofibril tangles – aggregates of Tau
Can have lots of tangles and be fine
Or little tangles and not be fine
PD
• PD (substantia nigra): Mitochondrial dysfunction
AD
• AD (entorhinal cortex and CA1): glucose and oxygen delivery
HD
•HD (medium sized spiny neurones of striatum): Cav1.3 channels Excitation controlled by glutamate from neocortex & DA from substantia nigra
MND
Excitotoxicity
How does neurodegeneration spread ??
Affected neuron can produce toxin and precipitates spread of toxic misfolded protein
All areas of brain susceptible to mitochondrial dysfunction
Proteins all tend to be what
amyloidogenic – sticky and stick to each other
What forms amyloid filaments ?
• b-amyloid, tau, a-synuclein, huntingtin and superoxide dismutase
Twisted, non-branching filaments composed of b-sheets
TDP-43
TDP-43 - pathological protein in ALS
Less amyloid like: amorphous, disordered aggregates…but it does have a prion like domain suggested to be necessary for amyloid formation
Creuzfelt Jacob disease
- prion disease - where prions first observed
• Prions are proteins that can adopt distinct conformations, at least one of which is self replicating
Evidence for prion-like spread mechanism 1:
a-synuclein pathology in grafted neurones.
- host to host graft spreading of lewy pathology in PD
- Patient recived a transplant of foetal mesencephalic dopaminergic nerve cells into the putamen 16 years previously
- immunohistochemistry for alpha synuclein visualises lewy bodies in host SN and the transplant
Evidence for prion-like spread mechanism 2:
Injection of tau and alpha synuclein results in disease-specific propagation of disease specific inclusions.
Multiple pathologies and pathology overlap:
MRC Cognitive Function and Ageing Study Aged persons brain has a bit of everything - Treatment Bespoke for the individual - Trials are limited – not realistic -
