Neurophysiology 3

Question 1

what is the pathology of Alziemhers disease?

Answer 1

• The main characteristic if the formation of amyloid beta plaques. These plaques are found intracellularly in the mitochondria and extracellularly as they are deposited outside.
• Another characteristic are neurofibrillary tangles which are made up of tau proteins. They are found within the cell (intracellularly

Question 2

what is the background of AD?

Answer 2

•	Most common form of dementia
•	Affects ~0.5 M in UK – highest risk factor
•	Incidence:
–	~1:50 (65y-70y)
–	~1:5 (>80y)
–	Higher incidence in females

Question 3

what are the 2 main types of AD?

Answer 3

early and late onset

Question 4

what is early onset?

Answer 4

pre 65y/o

Question 5

what is set to cause early onset?

Answer 5

o Mutations in genes encoding:
 Amyloid precursor protein (APP). This is a large protein produced in the brain and is chopped up into fragments to produce amyloid B
o Presenilin 1 (component of γ-secretase)
o Presenilin 2 (component of γ-secretase)
• Affects production of Amyloid B
Mutations in the genes will alter production of amyloid B, this is a insoluble from of amyloid so it will accumulate in the brain.

Question 6

what is late onset?

Answer 6

most common type 50-60% of all cases
cause of this is unknown but could be linked to apolipoprotein E (ApoE)  this transports cholesterol into neurones, produced by astrocytes within the body.

Question 7

what is ApoE?

Answer 7

It is also thought that ApoE binds to the Amyloid B and regulates aggregation/ plaque formation within the brain. There is a mutation to produce ApoE which produced ApoE4 and this variant is less effective at regulation aggregation thus forming more plaques in the brain, therefore making it a risk factor.

Question 8

what is the amyloid hypothesis?

Answer 8

The larger protein (AAP) is broken down to amyloid B which accumulates in the brain and causes Alzheimer’s.
Evidence for this is that the APP gene is found on chromosome 21, and those with down syndrome have an extra copy of this chromosome so they produce more APP. These individuals exhibit Alzheimer’s characteristics but the age of 40.

Question 9

what is APP processing?

Answer 9

APP is embedded in the plasma membrane. Normally APP is cut by alpha secretase and gamma secretease.
the gamma secretase can cut in 2 places, this produces fragmetns which are used in the brain

Question 10

where are the two place it gets cut?

Answer 10

40 and 42

Question 11

what are the fragments used?

Answer 11

the brain and they help in the synapse for learning and memory

Question 12

what happens if APP processing goes wrong?

Answer 12

The issue arises when the large protein APP is cut by the beta version of the enzyme instead of the alpha. This cuts it at the 1 place and gamma secretion cuts at the 42 place, this produces the fragment called amyloid B, this can clump together in the brain and cause plaques to be formed.
When beta secretase and gamma secretase cut together, they produce amyloid beta peptide which is 42mer long, this is an insoluble peptide

Question 13

what happens is amyloid B aggregate?

Answer 13

they form a toxic plaque within the brain and this leads to the disruption of neurone distribution and therefore causes cell death - the plaques formed and insoluble

Question 14

what is the tau hypothesis?

Answer 14

• Tau is a protein associated with the microtubules.
• The microtubules are long scaffolding structure which help support the cell and they are also a transport system within the cell which allows transport of nutrients and molecules.
• Phosphorylation happens a lot throughout the body, adding a phosphate group to a molecule. When you add phosphate to the Tau protein it helps to stabilise the microtubule

Question 15

what do problems arise in tau?

Answer 15

• The problems come when there is hyperphosphorylation on the Tau, this causes the microtubules to disintergrate and therefore nutrients can no longer be transported
• This then forms the tau proteins to tangle and prevent neuronal function  cell death

Question 16

what happens if tau is disrupted in the hippocampus?

Answer 16

this means it is difficult to from new memories, but you can still remember the older memories which were already formed

Question 17

what happens if tau is disrupted in the in the amygdala?

Answer 17

hard to recall memories

Question 18

what happens if tau is disrupted in the cortex?

Answer 18

the longer term memories are now beginning to be lost

Question 19

what are the two types of stroke?

Answer 19

ischemic and haemorrhagic stroke

Question 20

what is ischemic stroke?

Answer 20

• More common type
• The blood supply to the brain is disrupted
• This could be caused be a clot or plaque formed within the brain.
• In terms of treatment, life style advice (diet, exercise) if this doesn’t work then Rx Statins

Question 21

what is a haemorrhagic stroke?

Answer 21

• This is caused due to a bleed in the brain
• The best treatment is surgery to cut the clot and repair the burst blood vessels. This is called craniotomy.
• Blood pressire (ACE inhibitors and Beta blocks are also given alongside lifestyle advice

Question 22

what happens during a stroke?

Answer 22

– Cell deprived of nutrients and oxygen
– This leads to cell death and brain damage
– Quite often there are two areas a stroke can occur the inner area the Umbra, there is usually so much damage to this tissue that is cannot repair. The Penumbra which is the area around the core of the stroke and in this area, there is potential for recovery.

Question 23

what does a patient produce when they have a stroke?

Answer 23

When a patient has a stroke then they produce cytokine Interleukin 1B. this will cause inflammation of the brain and this exacerbates brain damage caused by the stroke.

Question 24

what does interleukin 1B do?

Answer 24

Interleukin 1 which binds to receptor and causes signalling within the cell, and tells the cells to produce more inflammatory cytokines (interleukin 6 and tumour necrosis factor), this exacerbates the damage to the brain  cell death.