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MED310 > Patterns and overlaps > Flashcards

Patterns and overlaps Flashcards

1
Q

What is Neurodegeneration ?

A
  • 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
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2
Q

Alzheimers pathology

A

Gyri wider and sulci narrow

- everything seems to shrink

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3
Q

HD pathology

A
  • Lateral ventricle bigger

In Basal ganglia – head of caudate convex to concave

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4
Q

MN

A

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

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5
Q

Astro gliosis – HD

A
  • 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
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6
Q

What is associated with a cognitive impairment?

A

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

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7
Q

Astrocytic plaques

A

Marked astrocytic reaction to beta amyloid plaques correlated with dementia phenotype

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8
Q

MN/ ALS :

Research

A
  • 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
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9
Q

Microglia

A
  • 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
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10
Q

M0

A

resting

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11
Q

M1

A

Killer/Classic activation

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12
Q

M2

A

Supportive and constructive wound healing

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13
Q

Microgliosis

A

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

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14
Q

common theme of neurodegenerative diseases

A

Deposits of protein

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

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15
Q

BRAK staging

A

stage of disease related to spread of tau

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16
Q

Protein deposits:

A
  • 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
17
Q

Ubiquitination

A

Large number of diseases characterised by ubiquitin aggregates

18
Q

What is another form of classification ?

A

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

19
Q

What is the cognitive phenotype related to ??

A

Area affected

- neurodegenerative disease can present with motor/cognitive or both

20
Q

Conditions of overlap

A

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

21
Q

PD

A

• PD (substantia nigra): Mitochondrial dysfunction

22
Q

AD

A

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

23
Q

HD

A

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

24
Q

MND

A

Excitotoxicity

25
Q

How does neurodegeneration spread ??

A

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

26
Q

Proteins all tend to be what

A

amyloidogenic – sticky and stick to each other

27
Q

What forms amyloid filaments ?

A

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

28
Q

TDP-43

A

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

29
Q

Creuzfelt Jacob disease

A
  • prion disease - where prions first observed

• Prions are proteins that can adopt distinct conformations, at least one of which is self replicating

30
Q

Evidence for prion-like spread mechanism 1:

A

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
31
Q

Evidence for prion-like spread mechanism 2:

A

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

32
Q

Multiple pathologies and pathology overlap:

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

MED310 (18 decks)

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