Patterns and overlaps

Question 1

What is Neurodegeneration ?

Answer 1

• 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

Question 2

Alzheimers pathology

Answer 2

Gyri wider and sulci narrow

- everything seems to shrink

Question 3

HD pathology

Answer 3

• Lateral ventricle bigger

In Basal ganglia – head of caudate convex to concave

Question 4

MN

Answer 4

motor neurone loss from anterior horns
Effects system of the musculature and motor functions
Loss of neurons

Question 5

Astro gliosis – HD

Answer 5

• 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

Question 6

What is associated with a cognitive impairment?

Answer 6

A Reduced Astrocyte Response to β-Amyloid Plaques in the Ageing Brain Associates with Cognitive Impairment.

Question 7

Astrocytic plaques

Answer 7

Marked astrocytic reaction to beta amyloid plaques correlated with dementia phenotype

Question 8

MN/ ALS :

Research

Answer 8

• 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

Question 9

Microglia

Answer 9

• 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

Question 10

M0

Answer 10

resting

Question 11

M1

Answer 11

Killer/Classic activation

Question 12

M2

Answer 12

Supportive and constructive wound healing

Question 13

Microgliosis

Answer 13

common feature of neurodegenerative disease and can modulate observed disease phenotype
-Ventral horn – MN
Motor axons – between microglia

Question 14

common theme of neurodegenerative diseases

Answer 14

Deposits of protein

– protein deposits begin in specific areas then continue to spread in a step wise place specific manner

Question 15

BRAK staging

Answer 15

stage of disease related to spread of tau

Question 16

Protein deposits:

Answer 16

• 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

Question 17

Ubiquitination

Answer 17

Large number of diseases characterised by ubiquitin aggregates

Question 18

What is another form of classification ?

Answer 18

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

Question 19

What is the cognitive phenotype related to ??

Answer 19

Area affected

- neurodegenerative disease can present with motor/cognitive or both

Question 20

Conditions of overlap

Answer 20

Neurofibril tangles – aggregates of Tau
Can have lots of tangles and be fine
Or little tangles and not be fine

Question 21

PD

Answer 21

• PD (substantia nigra): Mitochondrial dysfunction

Question 22

AD

Answer 22

• AD (entorhinal cortex and CA1): glucose and oxygen delivery

Question 23

HD

Answer 23

•HD (medium sized spiny neurones of striatum): Cav1.3 channels Excitation controlled by glutamate from neocortex & DA from substantia nigra

Question 24

MND

Answer 24

Excitotoxicity

Question 25

How does neurodegeneration spread ??

Answer 25

Affected neuron can produce toxin and precipitates spread of toxic misfolded protein All areas of brain susceptible to mitochondrial dysfunction

Question 26

Proteins all tend to be what

Answer 26

amyloidogenic – sticky and stick to each other

Question 27

What forms amyloid filaments ?

Answer 27

• b-amyloid, tau, a-synuclein, huntingtin and superoxide dismutase Twisted, non-branching filaments composed of b-sheets

Question 28

TDP-43

Answer 28

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

Question 29

Creuzfelt Jacob disease

Answer 29

- prion disease - where prions first observed | • Prions are proteins that can adopt distinct conformations, at least one of which is self replicating

Question 30

Evidence for prion-like spread mechanism 1:

Answer 30

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

Question 31

Evidence for prion-like spread mechanism 2:

Answer 31

Injection of tau and alpha synuclein results in disease-specific propagation of disease specific inclusions.

Question 32

Multiple pathologies and pathology overlap:

Answer 32

``` MRC Cognitive Function and Ageing Study Aged persons brain has a bit of everything - Treatment Bespoke for the individual - Trials are limited – not realistic - ```