13 - Neurodegenerative Diseases

Question 1

What are four neurodegenerative diseases?

Answer 1

Huntington’s Disease
Parkinson’s Disease
Alzheimer’s Disease
Cruetzfeld-Jacob Disease

All associated with progressive deterioration of brain tissue accompanying decline in functioning. Fatal.

Question 2

What are some treatments for Parkinson’s disease?

Answer 2

1. Dopamine agonist drugs (e.g. L-Dopa)
2. Cell Transplant Techniques (healthy dopamine cells are put into brain, poor results in Parkinson;s, but good in patients poisoned by MPTP)
3. Brain Lesions to GPi or STN (remove source inhibition to thalamus, so excitatory input to cortex increases)
4. Deep Brain Stimulation in STN (can control and titrate, isn’t permanent.

Question 3

Explain the neuro-chemistry of Parkinson’s Disease

Answer 3

Loss of SN neurons, and Lewy bodies in survibing neurons.

Lewy bodies contain aggregation of protein “alpha-synuclein” (due to production of misfolded protein as loss of function of “Parkin” protein which tags misfolded proteins so enzymes can destroy them.

Question 4

Explain the progression of Alzheimer’s Disease

Answer 4

Memory loss (especially recent, autobiographic)
Word-finding problems and difficulties with complex tasks
Inability to perform simple tasks (e.g. feeding) and further deterioration of language
Finally becomes vegetative

Question 5

Explain the neuropathology of Alzheimer’s Disease

Answer 5

Widespread loss of brain tissue in cortex

Severe degeneration of:

• hippocampus and entorhinal cortex
• “Association cortex”
• specific subcortical nuclei

Senile/amyloid plaques
Neurofibrillary Tangles

Question 6

Describe “Senile”/Amyloid Plaques

Answer 6

Collection of neural debris, particularly beta-amyloid (protein from cell walls)
Beta-amyloid precursor protein (APP) is normally chopped into 3 by secretase, with middle being beta-amyloid.
In Alzheimer’s brain, more long form beta-amyloid (~40%, normal <10%), which is misfolded and toxic.

Question 7

What forms the association cortex?

Answer 7

anterior temporal
posterior parietal cortex
prefrontal cortex

Question 8

What specific subcortical nuclei are affected by Alzheimer’s disease and what systems are they a part of?

Answer 8

nucleus basalis [cholingergic] -> most pharmacological treatments target this.
locus coeruleus [noradrenergic]
raphe nuclei [serotonergic])

Question 9

What are neurofibrillary tangles?

Answer 9

Clumps of tau protein detached from disintegrating microtubules (cytoskeleton) inside neuron

Question 10

Explain what pattern the distribution of plaque follows in the brain

Answer 10

Seems to form in main areas that are always activated.

Parts of the brain that are associated with not engaging with a task, as there’s continuous activity.

Metabolism is thus very high there, and plaques grow here.

Question 11

In an experiment, what reduced amyloid plaque and what did their results show?

Answer 11

Used anti-body aducanumab that destroys beta-amyloid.

Treatment with anti-body; less and less beta-amyloid with increasing dose.
Also affects cognitive function; everyone’s dementia worsened, however increase dose of anti-body showed slower decline. Placebo show strong deterioration.

Question 12

What is Cruetzfeldt-Jakob Disease (CJD)?

Answer 12

Progressive degeneration (months-years) disease, manifesting in neurological dysfunction (mainly loss of coordination and dementia)

Very low occurence, 1 in a mil

Progression typically faster than Alzheimer’s

Post-mortem shows brain like a sponge, full of small holes -> spongiform encephalopathy.

From prions

Question 13

How were prions found to exist and cause CJD?

Answer 13

Kuru tribes; would eat dead brains of people who had died from brain disease, and those people would get disease and die.

Iatrogenic (caused by medical treatment) cases of CJD-
infectious material not affected by procedures that destroy nucleic acid.

So, agent of CJD did not have DNA or DNA
But, material was affected by procedures that denatured or destroyed proteins.

Question 14

Where do prions come from

Answer 14

Known sequence of AA in prion protein (PrP).

All animals carry genes that codes for PrPs, but varies slightly across species, and difference increases with greater evolutionary distance.

Basis for species barrier to disease (disease that makes cow sick won’t make human sick, normally)

Question 15

What are the two types of PrP?

Answer 15

Normal form: degraded by appropriate enzymes

Aberrant Form: resistant to usual enzymes, forms that causes disease.

They both have different genetic codes, but same AA sequence. Differ in 3D structure

Question 16

Describe the experiment with mice that demonstrates the infectiousness associated with PrP’s

Answer 16

Healthy mice injected with material from brains of diseased mice, develop encephalopathy and die.
But, infectious PrP does NOT cause disease in mice that lack PrP gene.

So, infectious protein must have normal PrP present in cells to cause disease. Aberrant PrP can convert normal PrP to have aberrant tsructure.

Question 17

How did the Mad Cow outbreak occur in Britain?

Answer 17

Due to change in dietary supplement for cows caused Mad cow, or BSE (bovine spongiform encephalopathy). Included parts of sheep brain matter

Species barrier between cows and sheep not large, but larger between cows and humans.

Infectious PrPs from BSE cows can cross epcies to infect mice, pigs and primates, so might be able to cross into humans.