Alzheimer's disease

Question 1

Which gene increases the risk of developing late-onset alzheimer’s disease?

Answer 1

The E4 sub-type of the Apolipoprotein E4.

Question 2

Name some diagnostic tools used for Alzheimer’s disease detection?

Answer 2

1. Brain scanning and imagery (CT, MRI etc).
2. Blood tests are being developed
3. Psychological and memory tests are also being developed.

Question 3

Name the three main pathological markers in the brain that are indicative of Alzheimer’s disease?

Answer 3

1. Neurofibrillar tangles inside the neurons from hyperphosphorylated Tau proteins.
2. Amyloid plaque deposition on the outside of these neurons.
3. Amyloid plaque deposition on the outside of blood vessels in the brain.
4. Severe atrophy of the brain at later stages in the disease.

Question 4

What is the pathological basis for dementia in Alzheimer’s patients?

Answer 4

It is believed that the loss of synapses, rather than amyloid plaque deposition results in dementia development.

Question 5

What are amyloid plaques comprised of?

Answer 5

Amyloid plaques contain aggregated amyloid beta protein. They also contain lots of metal ions and are associated with secondary inflammation and neuronal dysfunction.

Question 6

What are neurofibrillar tangles comprised of?

Answer 6

Neurofibrillar tangles are aggregated, hyperphosphorylated Tau proteins inside the neurons. It is the hyperphosphorylation of the tau proteins that causes it to become insoluble, so it aggregates inside the neuron.

Question 7

What causes the neuroinflammation in the brain that causes this neuronal dysfunction?

Answer 7

1. Activation of resident macrophages in the brain that were otherwise resting.
2. Infiltration of systemic monocytes into the brain.
3. Both of the immune responses above occur in response to the increased amyloid and tau aggregation.

Question 8

How do free radicals contribute to Alzheimer’s disease?

Answer 8

Free radical species cause peroxidation of lipids, DNA and proteins in the brain, causing damage.

Question 9

Describe the amyloid beta protein.

Answer 9

The amyloid beta protein is the one that aggregates outside the neurons during Alzheimer’s disease. The term ‘amyloid’ was given to it because the protein aggregates in a special shape. It forms aggregates with a distinct structure and shape, like starch and cellulose.

Question 10

What are the characteristics of the amyloid plaques?

Answer 10

1. They have congo red birefringence (they are red under normal light but green under polarized light)
2. It forms oligomeric plaques with beta helix protein arrangement.
3. It is insoluble and protease resistant.

Question 11

How is the amyloid beta protein formed?

Answer 11

It is formed by being cleaved from the larger protein called the Amyloid precursor protein. The enzymes beta-secretase and gamma-secretase cleave it to form amyloid beta peptide.
The amyloid beta protein is usually in the alpha helix form and is converted to the beta-sheet form when aggregated.

Question 12

Alzheimer’s patients have been found to have altered biometal metabolism in their brains. What does this mean?

Answer 12

There are high amounts of extracellular copper and zinc. There are also very low levels of copper inside the neuron. Normally, amyloid beta protein binds copper and zinc ions at histidine and tyrosine residues. This process doesn’t happen in the Alzheimer’s brain.
These biometals also cause the formation of cross linkages between the amyloid aggregates so that they are harder to degrade.

Question 13

Why does amyloid beta protein accumulate so many biomentals?

Answer 13

The amyloid beta plaques utilise the metals for their own formation of oligomer plaques. They use the copper and zinc ions to also activate proteases

Question 14

How do the amyloid beta plaques induce pathology?

Answer 14

They induce pathology via the amyloid plaque toxicity. This is when the accumulation of the amyloid plaque aggregates on the extracellular surface of the neurons disrupts synaptic and axon functioning.

Question 15

What are the pathway mechanisms that amyloid beta plaques take to induce neuronal dysfunction?

Answer 15

1. Accumulation of plaques inside the neuron.
2. Synaptic and axonal toxicity
3. Aberant (altered) cell signalling leading to cellular chaos.
4. ER stress state (UPR gene expresses)
5. Glutamate excitotoxicity (too much glutamate stimulation)
6. Decreased cellular energy production via damaged mitochondria
7. Inhibit neuronal support from glial cells
8. Damage from inflammation
9. Neurofibrillar tangles (hyperphosphorylated tau protein)
10. Inducing oxidative stress in the neuron via the NMDA glutamate receptor.