L24 - Neurodegenrative Diseases

Question 1

What is a neurogenerative disease? Examples?

Answer 1

• All neurodegenerative diseases have a deterioration of brain tissue and accompanying decline in functioning
• All fatal in terms of decline making the individual more vulnerable to other things (e.g. pneumonia)
• Varied time lines
• All associated with age (at least the examples)
  
  • Huntington’s
  • Parkinson’s
  • Alzheimer’s
  • Creutzfeldt-Jacob Disease

Question 2

What is Creutzfeldt-Jakob disease (CJD)?

Answer 2

• Progressive degenerative disease (months, sometimes > 1 year) manifesting in neurological dysfunction (mostly loss of coordination and dementia)
• Rare: about 1 in 1,000,000 per year
• Quite fast progression of decline compared to other diseases
• On postmortem, brain full of small holes -“sponge” “spongiform encephalopathy” - only sponge disease in humans (also scrapie, BSE and others)
• New type of infectious agent known as prions

Question 3

What is the infectious agent in Creutzfeldt-Jakob disease?

Answer 3

• Can be genetic (familial) but often more sporadic, but also by infection…
  
  • Kuru (version of this disease common among certain tribes in New Guinea)
    
    • iatrogenic cases of CJD: Infectious material (from brains) - in the tribes culture to eat the brains of their dead elder
    • Some cases where CJD crossed from patients during surgery
• Not affected by procedures that destroy nucleic acids
• Therefore agent did not have DNA or RNA
  
  • (ie, not like living pathogens - viruses, bacteria etc)
• Infectious material was affected by procedures that denatured or destroyed proteins
• “Prion” = Infectious Protein - (Protein infection = Prion)

Question 4

Where do Prions come from?

Answer 4

• Known sequence of amino acids in the prion protein (PrP):
• Discovered that all animals carry genes that codes for PrPs
• Slightly different across species, and difference increases with greater evolutionary distance between species.
  
  • Basis for species barrier to disease

Question 5

What are the different forms of PrPs?

Answer 5

• All have prion proteins
  1. Normal form (degraded by appropriate enzymes)
  2. Aberant form (that is resistant to usual enzymes) → form that causes disease
• Different genetic codes but same amino acid sequence
• Two PrPs differ in 3D structure depending on how amino acid chain is folded up
• Aberrant form has misfolded structure that makes it resistant to normal enzymes - not being removed so accumulates inside the cell leading to the death of a neuron

Question 6

What is the infectiousness like in CJD?

Answer 6

• Healthy mice, injected with material from brains of diseased mice, develop encephalopathy and die.
• But infectious PrP does NOT cause disease in mice that completely lack PrP gene
  
  • thus infectious protein must have normal PrP present in cells to cause disease - making your own PrP is necessary
• Misfolded PrP can convert normal PrP into misfolded form

Question 7

What was mad cow disease and CJD like in Britain?

Answer 7

• Outbreak of BSE due to change in dietary supplement for cows
• Species barrier between cows and sheep not so large (PrPs differ at only 7 places), but much larger between cows and humans (PrPs differ at 30 places)
• Shown in that infectious PrPs from BSE cows can cross species barriers to infect mice, pigs, and primates
  
  • Thus maybe can cross into humans
• But no BSE in Australia, and PrPs virtually absent in skeletal muscle (i.e. steak is ok)

Question 8

What is Huntington’s disease and the cause?

Answer 8

• Brains of HD sufferers: death of GABAergic cells in striatum (largely autosomal disease)
• HTT gene on chromosome 4 codes for Huntingtin protein expressed in all cells but particularly high in neurons
• HD sufferer has longer DNA sequence on HTT which creates mutant Huntingtin protein
• Breakdown of mutant protein produces short fragments that get misfolded and form aggregates that are toxic, leading to the death of the cell
  
  • Only exists as a genetically determined thing

Question 9

What is Parkinson’s disease and the cause?

Answer 9

• Brains of PD sufferers have a loss of substantia nigra neurons and lewy bodies in surviving neurons
• Lewy bodies contain aggregation of protein “α-synuclein”
  
  • Production of a misfolded alpha-synculein protein
    
    • Loss of function of “parkin” protein that tags misfolded proteins for destruction by enzymes
• No gene yet that has shown to be responsible for parkinson’s disease
• Has multiple different causes which is why it is more prevalent

Question 10

What is Alzheimer’s disease? What is the neuropathology?

Answer 10

• 50% of all dementia cases
• Neuropathology
  
  1. Widespread loss of brain tissue in cortex or shrinkage of the brain
  2. • First stages of the disease most commonly occur around the hippocampus and temporal lobe - this is why memory deficit is often the first symptom
       - Normally recent memories that are impaired but good memories for the distant past
• Severe degeneration of
  
  • hippocampus and entorhinal cortex;
  • “association” cortex (anterior temporal and posterior parietal cortex; prefrontal cortex);
    
    • Areas involved in higher cognitive functions
    • Motor areas are normally not as affected but more so issues of attention, ability of planning
  • specific subcortical nuclei: nucleus basalis (cholinergic), locus coeruleus (noradrenergic), raphe nuclei (serotonergic).
    
    • One opportunity for treatment - pharmaological treatment that inhibits AChE - can reverse some of the cognitive decline

Question 11

What pathological material do we see present in those with Alzheimer’s disease?

Answer 11

• Brain tissue full of
  
  1. Amyloid (”senile”) plaques
     
     1. Collection of neural debris, particularly high concentration beta-amyloid (a protein found in cell walls)
     2. In normal brain
        
        1. β-amyloid precursor protein (APP) chopped into 3 pieces by secretase enzymes.
        2. In normal brain, >90% of β- amyloid is short (40 AAs) and <10% is long (42 AAs).
        3. In Alzheimer brain, more long form (up to 40%), misfolded and toxic.
     3. Treatments being developed using antibodies to eliminate these proteins

2. Neurofibrillary tangles
   
   1. Clumps of tau protein detached from disintegrating microtubules (cytoskeleton) inside neuron

Question 12

How are beta-amyloid plaques distributed in the brain?

Answer 12

• Not uniformly distributed
• Mostly in frontal lobes, posterior parietal lobe and anterior part of temporal lobe as these are the areas where there is the greatest loss of neurons + loss of function in the areas
• The areas of beta-amyloid show an overlap with the area of the default-mode network

Question 13

What are the treatments for Alzheimer’s disease?

Answer 13

• AChE inhibitors (e.g. donazepil [Aricept]):
  
  • Can produce some improvements in cognitive function, particularly in relatively early stages of disease.
• Non-competitive NMDA antagonist (memantine):
  
  • Shown to recover some cognitive function in more advanced stages of disease (moderate to severe).
  • Non-competitive - doesn’t bind to glutamate binding site
  • Want NDMA to be precise but in Alzheimer’s their effect becomes too non-specific so increasing noisy activity within the brain
• Monoclonal antibodies (“mabs”, e.g. aducanumab, lecanemab):
  
  • in clinical trials shown to eliminate β-amyloid and hyperphosphorylated tau, but evidence for cognitive/therapeutic benefit unclear (and high incidence of side effects - such as brain swelling - may have to have frequent brain scans).
  • Not really having the clinical benefit
  • Won’t reverse the disease by eliminating these

None of these treatments are easy to administer. Happen via injection and have to visit doctors to get injection