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BIOL3043 - Cellular and molecular pathology > Lectures 15 & 16 - Neurodegeneration > Flashcards

Lectures 15 & 16 - Neurodegeneration Flashcards

1
Q

Define neurodegeneration

A

The loss of neurons, where neurons are dying because of disease or some other process

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2
Q

Describe features of chronic neurodegeneration and example of diseases

A

Slow onset
Progressive
Last for many years

Diseases:
-Alzheimer’s Disease
-Parkinson’s Disease
-Multiple Sclerosis
-Prion Disease

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3
Q

Describe features of Acute neurodegeneration and examples

A

Sudden onset
Secondary progression after initial incident
Generally patients quite healthy prior
Associated with a trigger event

Examples:
-Traumatic Brain Injury
-Stroke
-TIA (transient ischaemic attack)
-Intracranial Haemorrhage

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4
Q

Describe statistics and features of strokes

A

Events of stroke are generally similar across all acute comditions (apart from traumatic brain injury)

4th most common cause of death in UK – 5% men, 8% women

152,000 strokes every year (100,000 are first strokes)

Two thirds will survive

Largest cause of severe disability (500,000+)

31% of survivors need help caring for themselves, 71% have speech impediments and 16% have to be institutionalised

1 in 53 people in the UK (1.2million people) are “stroke survivors”

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5
Q

Describe the prevalence and risk of strokes

A

Incidence doubles every decade after 55

Ageing population leading to increased prevalence

Strokes more common in men but more women die

Lower risk in caucasian population compared to many other ethnic groups

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6
Q

Explain the stroke mortality trend in the UK

A

Mortality reducing due to improved clinical pathways, wider access to specialist stroke wards and increased public and professional awareness (e.g. FAST campaign)

Number of cases affected by a number of modifiable risk factors:

– Hypertension (increasing/100000 population)

– Diabetes (type II increasing/100000 population)

– Hypercholestrolaemia (managed effectively by statins etc)

– Previous stroke or transient ischaemic attack

  • BUT ageing population means overall prevalence is still high
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7
Q

What do we mean by stroke?

A

blood supply to part of the brain has been interrupted

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8
Q

What are the different types of stroke?

A

Ischaemic Stroke:
-85% of all strokes ≈ 30% Mortality
-Ischaemia – loss of blood supply
-Blood vessel that delivers blood to region of brain has been blocked by something
-signs and symptoms directly relate to which blood vessel is being blocked

Haemorrhagic Stroke:
-15% of all strokes ≈ 70% Mortality
-Artery bursts – blood leaking into brain from artery and any brain tissue that would’ve received blood from that arteries is now not receiving

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9
Q

What is the most common blood vessel affected in strokes

A

Middle cerebral artery (>50%)

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10
Q

What happens in a stroke where the middle cerebral artery is blocked?

A

blood flows up from outside the brain and then upwards towards the top of the brain, depending on where you block the artery will have different effects

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11
Q

What is the deterioration or recovery from a stroke partially dependable on?

A

If there’s tissue that’s rescuable then there’s slight recovery, balance of this is dependent on how much blood supply there is to the surrounding tissue

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12
Q

What happens to a structural lesion after a stroke

A

After a few hours and days the surrounding tissue will start to pull more blood and oxygen from other blood vessels, eventually after a week or so, you end up with a structural lesion, the core area of tissue, made up of dead neurons and astrocytes, being carried away by microglial cells

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13
Q

Explain how neurodegeneration occurs in stroke

A

Stroke = loss of blood supply
Loss of blood supply = Loss of oxygen and glucose due to lack of energy store
leaidng to energy faikure (cells loose the ability to make ATP) this leads to:
-Loss of protein synthsis – decrease in protective proteins
-faulure of Na+/K+ ATPase – therefore depolarisation
-Anaerobic metabolism – decrease in pH

This depolorisation leads to calcium influx and neurotransmitter release (glutamate)

Also presents of lactate from anaerobic metabolism causes calcium influx into the cell

Calcium is toxic for a number of reasons:

Triggers activation of enzymes e.g. proteases that break down the cytoskeleton and lipases that break doen the cell membranes

Cytotoxic oedema – water drawn into cell, it swells up and can cause the cells to explode, or blockge of more blood vessles

Go intonmitochondria and produce free radicals

Other things

If unregulated these things lead to cell death

Reperfusion:

Cell death and inflammatory response created allow reprofusion

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14
Q

Explain the mechanisms of neurodegeration from excitotoxicity

A

Death by overexcitation of cells, incraesed calcium therefore increased glutamate

Leading to cell death

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15
Q

Explain the mechanisms of neurodegeration from free radical toxicity:

A

Increased calcium from depolarisation leads to increased free radicals, leading to cell death

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16
Q

Explain the experimental evidence that showed depolarisation and glutamate release in strokes

A

done in rats

probe into the brain - measured the amount of glutamate released in ten minute time windows

injected endothelium 1 (ET1) - a vasoconstrictor into the Middle cerebral artery
blood flow through it stopped - an experimental model of stroke

the amount of glutamate that was released into the brain went up very quickly and very significantly

confirms depolarisation and glutamate release in strokes

added drug called LY377770 (blocks calcium release) therefore because there was major decrease in glutamate release when this drug present, further conforms calcium drives the glutamate release

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17
Q

Explain the extra part of the experimental stroke model that showed that glutamate is toxic

A

When drug LY377770 was added, the size of lesion in the brain was greatly reduced

This drug blocks calcium release and therefore glutamate release, and so shows that glutamate is toxic

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18
Q

Explain an experiment that showed that glutamate antagonists are neuroprotective

A

MK-801 is a NMDA receptor antagonist (blocks it)
glutamate can still bind but with MK-801 there calcium isn’t allowed through
experiment sh0wed if you block NMDA receptors then you reduce to nearly nothing the amount of brain tissue lost

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19
Q

What does AMPA mimic the effects of?

A

Glutamate

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20
Q

What happens if you inject AMPA directly into the brain?

A

It activates AMPA/Kainate receptors, causing cell death

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21
Q

What happens if you inject NMDA directly into the brain

A

Cell death, caused by activation of NMDA receptors

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22
Q

What happens if you inject Glutamate directly into the brain?

A

nothing happens (no cell death) due to glutamate being he endogenous neurotransmitter, brain is good at removing it, glutamate itself is not toxic

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23
Q

Explain an experiment that shows the potentiation of glutamate toxicity

A

Cells exposed to a dye, that will glow orange of the cell dies.
normal untreated - cells alive
Expose cells to hypoxia for 60min(remove oxygen but leave glucose) - cells dont die
add 1mM Glutamate - cells surivie also
now together - same ampunt of glutamate and same period of hypoxia - all the cells start to light up

presence of both glutamate and lack of oxygen that makes the glutamate toxic

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24
Q

Explain why glutamate becomes toxic in stroke/hypoxic conditions

A

Due to lack of glutamate transporter function
Transporters for uptake of glutamate function by co-transport with sodium, so a sodium gradient is needed for it to functin. In hypoxic conditions, this gradient isnt present. and tehfore glutamate stays in the synaptic cleft and causes signals to be sent though the brain, leading to a stroke

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25
Q

What enzymes are free radicals regulated by in neurons?

A

Superoxide dismutases (Cu/ZnSOD, MnSOD)
Glutathione peroxidase

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26
Q

If free radicals aren’t regulated, what happens?

A

React strongly with lipids, proteins and nucleic acids which results in cell death
In particular bind to lipids start a chain recation that breaks down the cell membrane

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27
Q

Explain how calcium overload in ischemia leads to the build up of free radicals

A

Calcium gets taken up into the mitochondria which the affets all of the enzyme processes within the mitochondria, causing the mitichomdria to depeolorise

This has a number of effects:
- drives production of ROS (free radicals that contain oxygen)
- breakdown of xanthine
- nitric oxide production
these all lead to overproduction of free radicals, particularly ROS and particularly superoxide (-radical-O2minus) also interested in nitric oxide

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28
Q

how is Nitric oxide formed?

A

By nitric oxide synthase (NOS)- converts arganine into -radical-NO + Citrulline + H20
Called a specific type of NOS depending on where
put letter at start:
Endothelial = eNOS
Neuronal = nNOS
Inducible = iNOS
Mitochondrial = mtNOS

29
Q

Explain how the free radical nitric oxide itself isn’t that toxic, and when it does become toxic

A

Can diffuse into and out of mitochondria, not that toxic
becomes toxic when interacting with superoxide to form peroxynitrate which is highly toxic:
-radical-NO + O2- —> -radical-ONOO-

30
Q

Explain an experiment that shows the role free radicals play in neurotoxicity

A

neurons, incubated with a dye that glows green when free radicals are present

In control cells - small amounts of free radicals inside mitochondria

Remove oxygen and glucose from cells - within 5 mins lots of free radicals produced - across whole cell body, not limited to mitochondria

number of neurons that die in ischemia is high

block nitric oxide production by L-NAME
or Block supoeroxide production by TEMPO

toxicity goes down in both cases, showing you need both for free radical toxicity

31
Q

When is acute treatment used for stroke, and what are the desired outcomes?

A

used just after someone has had a stroke. Hopefully reduce neuronal degradation and early mortality. unfortunatly there are very little acute treatments available for strokes

32
Q

What drug is used to treat stroke?

A

Tissue plasminogen activator (tPA) - activates fibrinolysis to allow the body to breakdown the clot thats blocking the artery and return blood flow

Edarovone (a free radical scavenger) - licensed in japan only - none of the US and UK trials showed efficacy

33
Q

What is the original trial data for the r-tPA trial (1995)

A
  • 30% more likely to have minimal or no disability after 3 months than placebo
  • 1.7x more likely to have a better outcome than placebo
  • 17% mortality at 3 months vs 21% in placebo
  • BUT: 6.4% of r-tPA-treated patients had an intra-cerebral
    haemorrhage within 36 hours compared to 0.4% in placebotreated patients
34
Q

Explain features of tPA

A
  • Age limited (18-79); multiple contraindications
  • Requires absolute certainty that there is no intracranial bleeding
  • Very limited time window of efficacy (within 4.5hrs of onset)
  • Very small percentage (12-20%) of patients actually receive r-tPA
    (Alteplase)
35
Q

Explain some drugs to treat stroke that made it to clinical trials but showed no efficacy

A

Selfotel - NMDA antagonist
YM872 - AMPA antagonist
Nimodipine - Ion channel modulator
Cerovive - Free radical scavenger

36
Q

Why do so many stroke drugs not show efficacy in clinical trials/not have effect in preventing stroke

A

Most mechanisms occur within 2-3 hours of the onset of stroke
Usually strke occurs in more elderly person, living alon or have a stroke in the night ad have no contact with people
likely they wont get inti a clinicak managment situation within the time window that these events are occuring

37
Q

Why are outcomes of stroke drugs that didn’t show efficacy in clinical trials for humans good in animal trials

A

In animals - drugs effective if you pretreat before you start stroke, or give drug immediately after, in a real world clinical situation, very difficult to get drugs into patients in this early time period

38
Q

Whats is a potentail second area for drug targets in stroke?

A

Inflammation that happens after initial excitatory period

39
Q

What has reduced the time for people to be seen for stroke?

A

FAST campaign and better treatment planning within hospitals, means time windows where drugs would be effective may be possible

40
Q

What is initial lesion expansion in stroke due to?

A

Mechanisms that occur first e.g. glutamate toxicity, free radicals ect.

41
Q

What are the changes in size of lesion after the first few hours due to?

A

Ongoing chronic inflammation, secondary processes

42
Q

Explain gene expression following ischaemia

A
  1. Activation of immediate early genes (IEG) e.g. C-fos, C-jun - these genes drive transcription of other genes
  2. Expression of heat shock proteins (HSP) - HSP-70, HSP-72 - stress proteins - activated in cells in times of stress - stop protein degreadation/correct protein shape
  3. Expression of:
    -pro-inlammatory cytokines - TNF-a, IL-1b, IL-6
    -Adhesion molecules - ICAM-1, P-selectins - expressed on blood vessles and used to recruit circulating inflammatory cells into tissues
    -Growth factors e.g NGF, BDNF, expressed prodominantly by neurons but also by astrocytes and microglia - these are survival factors for neurons

Much later on - protease inhibators and remodelling factors, expressed as a way to try and grow new blood vessles and remodel the tissue thats been changed

43
Q

Explain the recruitment of inflammatory cells following ischaemia

A

Circulating inflammatory cells get recruited:
- PMNs, monocytes and macrophages
- quite delayed compared to a peripheral injury where you’d expect these cells to be recruited very quickly (brain much slower)

44
Q

In normal conditions of the brain, what do cytokines do?

A

There are NO cytokines expressed, they’re only expressed as a response to a stroke (e.g.)

45
Q

Explain the peripheral inflammatory response

A
  • expression of adhesion molecules
    -recruitment and activation of phagocytes
    -increase vascular permeability
    -all driven by cytokines
46
Q

Explain the CNS inflammatory response

A

-upregulation of cytokines
-inflammatory response delayed by hours-days
-Local activation of microglia - to start removing damaged tissue and generate scar tissue
- DON’T get significant tissue swelling - due to brain being in skull - no way for it to expand, if it did it would lead to increased intercranial pressure - BAD

47
Q

Describe features of Interleukin - 1b

A
  • predominant form of IL-1 in the brain
  • formed by activation of IL-1 converting enzyme (caspase 1)
  • Binds to specific IL-1 receptors (IL-1R) - associated with increased neuronal death
48
Q

How is the binding of IL-1b to IL-1Rs associated with neuronal cell death

A

increases permeability of endothelial cells
upregulates adhesion molecules
causes proliferation of astrocytes and microglia
production of prostoglandins
production of Nitrous oxides
induces other cytokines e.g. TNF-a

49
Q

What is the endogenous inhibitor of IL-1R?

A

IL-1ra (IL-1 receptor antagonist)

50
Q

Explain an in vitro experiment that shows the role of IL-1

A

Cell culture:
- Control conditions: Oxygen and glucose deprivation from cells to mimic ischaemic conditions
Results:
control - small amount of cell death
adding IL-1 - significant increase in cell death
adding IL-1ra - same as control
IL-1ra and IL-1 - slightly lower than control, shows it was mediated through IL-1R

51
Q

Does IL-1 cause neurodegenration on ots own?

A

NO - it needs to be in ischaemic conditions e.g. stroke
if you injected someone with IL-1 it would make them feel bad but no neurodegeneration would occur

52
Q

Explain an in vivo experiment that shows IL-1 causes neurodegeneration in stroke

A
  • Done in mice
  • control conditions - middle cerebral artery occlusion
    control conditions cause tissue damage
    Increasing levels of IL-1ra = neuroprotective
    tells you that its blocking the effects of IL-1 thats released from the tissue
    if you use too much IL-1ra you get a ‘rebound effect’ which is suggestive of something more complex going on
53
Q

What is IL-1ra licensed clinically to treat? what may it treat in the future if clinical trials are successful?

A

Treats rheumatoid arthritis
may treat stroke in future

54
Q

Explain the clinical trail undergone to see of IL-1ra could be used to treat stroke

A

patients who had a clinically defined stroke and who arrived in A&E within 6 hours of the onset of symptoms were randomly allocated to a placebo group or a 72hr infusion with IL-1ra

3 months later they were assessed:

two sets of data collected:
- Barthel index
- modified rankin scale
both measures of how independent a person is, further up on scale, more independent you are

Results:
proportion of most independent patients was higher for treated group
had no effect at all on patients who were more severely affected by initial strokes

its able ton improve quality of life of patients who had some effects of the stroke, but of you had a more serious stroke it had no effect

55
Q

Explain how in certain contexts its been seen that IL-1 is neuroprotective

A

– increase glial activation and proliferation
– induce synthesis of nerve growth factor
– enhance neuronal sprouting
– promote neovascularisation
– decrease calcium entry into neurones
– enhance GABA activity
* ….all of which may be neuroprotective

56
Q

Why May the certain contexts that IL-1 is neuroprotective in, not be correct?

A

could be an artefact of In vitro systems, they don’t have blood circulating, context may be different in body
experiments generally requires pre-treatment for several hours
– IL-1 not usually increased in the brain prior to ischaemia

57
Q

What raises red flags about completly blocking IL-1?

A

IL-1 was seen in some in vitro experiments to pose neuroprotective effects
dosage with toon much IL-1ra may block some of these secondary processes that are happening

58
Q

What is the link with TNF-a and neuroprotection/degeneration?

A

There is no confirmed view, literature has shown both neuroprotective and neurotoxic effects

59
Q

How is TNF-a neuroprotective (experiments)

A

TNF receptor KO mice - increase infarct (necrosis):
Bruce et al 1996, Nature Med 2:788

TNF decreases glutamate toxicity in vitro:
Cheng et al 1994, Neuron 12:139

60
Q

How is TNF-a neurotoxic (experiments)

A

TNF increase infarct volume - MCAO:
Barone et al 1997, Stroke 28:1233

TNF binding protein decrease infarct volume
Dawson et al 1996, Neurosci Lett 218:41

61
Q

Explain experimental procedures showing pre-treatment with TNF is neuroprotective in ischeamia

A

Cultured hippocampal slices exposed to experimental ischaemia, assessed 24 hrs post ischaemia

Control - showed some cells dead
Pretreated cells with TNF for 24 hours before inducing ischaemia - amount of cell death significantly reduced

62
Q

Explain experimental procedures showing post-treatment with TNF is neurotoxic in ischeamia

A

Cultured hippocampal slices exposed to experimental ischaemia, assessed 24 hrs post ischaemia

Control - showed some cells dead

if you delay addition of TNF to after the period of ischemia (and still allow the cells to recover for 24 hours) get recruitment of cells which would normally survive in this region and causes them to die.

63
Q

Is TNF itself neurotoxic in stroke?

A

no - but it can recruit cells to places where they will die - thus neurotoxicity

64
Q

Describe part of the process of TNF signalling

A

TNF Activates transcription factor NFkB which causes many gene expressions

under normal situations:
mitochondria are producing ROS
ROS signal NFkB activation which then causes gene transcription
one thingthat it drives trascriptiob of is mnSOD which detoxifies free radicals
therfore negative feedback loop

Under NfkB activation by TNF:
increases superoxide in mitochondria (process not 100% known)
which then increases the drive of trabscripton factors (p65, p50) which increases mnSOD therforeb the effect of the feedback loop is increased

65
Q

Explain why in pre-treatment with TNF, neuroprotection occurs

A

Enough time for the TNF signalling cascade to occur and therefore superoxide dismutases to be made

66
Q

Explain why in post-treatment with TNF, neurotoxicity occurs

A

ischaemia produces superoxides (ROS)
addig TNF which is adding the additional burden of ROS into the cell, causing cells that would normally survive the initial ischaemia to have this extra burden of superoxide production, which is then leading to cell death

67
Q

Whats the main difference between stroke and traumatic brain injury

A

stroke affects people of older age
brain injury affects predominantly under 35s

68
Q

Explain an experiment done to measure cytokine levels in traumatic head injury

A

cerebral microdialysis:

Used a microdialisis probe to take out extracellular fluid frim around the injury and measure cytokines produced by the brain around the injury
determined concentration of IL-1, IL-6 and NGF

Outcome:
measurments standardised on the glasgow outcome scale -5pt scale depending on how well you recover post-injury
results:
IL-1 didn’t have any difference on outcome
NGF - also no significant difference
IL-6 - patients with high IL-6 was a predictor for a good outcome

this was surprising as IL-6 is pro-inflammatory

Winter et al. (2004)

BIOL3043 - Cellular and molecular pathology (11 decks)

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