FunMed Week 6: AD

Question 1

Aggregation of beta amyloid peptides contributes to the formation of amyloid plaques in the brains of Alzheimer’s patients.

Briefly describe the proteolytic processing that the APP undergoes to produce the cytosolic beta amyloid peptide [2]

Answer 1

The transmembrane APP is first cleaved extracellularly by beta secretase to produce a membrane tethered peptide.

This is followed by intramembrane cleavage by g secretase to produce the beta amyloid peptide.

Question 2

1. (i) Which posttranslational modification does the microtubule-binding protein, tau undergo which contributes to Alzheimer’s pathology? (1/2 mark)
   (ii) Which amino acids can undergo this specific post translational modification?

Answer 2

Hyperphosphorylation.

Tyrosine, serine and threonine.

Question 3

1. Describe the secondary structure of amyloid fibrils. (1 mark)

Answer 3

Anti-parallel (1/2 mark) beta sheets (1/2 mark).

Question 4

1. AD typically destroys neurons and their connections in the entorhinal cortex and hippocampus.

What cognitive deficit would be observed in these patients?(1 mark)

Answer 4

Memory loss. (1 mark)

Question 5

1. Identify two CNS glial cells and describe their function. (3 marks)

Answer 5

Astrocytes (1/2 mark) protect neurons by filtering nutrients out of the blood (1/2 mark) and preventing chemicals and pathogens from leaving the capillaries of the brain (1 mark).

Oligodendrocytes (1/2 mark) wrap the axons of neurons in the brain to produce the insulation known as myelin (1/2 mark) . Myelinated axons transmit nerve signals much faster than unmyelinated axons, so oligodendrocytes accelerate the communication speed of the brain. (1/2 mark)

Microglia (1/2 mark) act much like white blood cells by attacking (1/2 mark) and destroying pathogens that invade the brain (1/2 mark).

Ependymal cells (1/2 mark) line the capillaries of the choroid plexuses (1/2 mark) and filter blood plasma to produce cerebrospinal fluid (1/2 mark).

Question 6

1. What is the difference between grey and white matter in the CNS? (1 mark)

Answer 6

Gray matter is mostly neuronal cell bodies and glial cells.

White matter is made up of myelinated axonal tracts (axons)

Question 7

describe how amyloid plaques are formed

Answer 7

amyloid plaque protein (APP):

• APP is cleaved by secretases:
• a , b and y secretase
• If cleaved by a + y - secretases ->> non-amyloidogenic pathway
• If cleaved by b + y - secretase ->> amyloidogenic pathway.
• The b + y secretase pathway will give rise to the AB peptide - two isoforms AB 40 and AB 42.
• The AB peptides will form fibrillar insoluble plaques between the neurons.
• The longer AB42 will be more fibrillogenic and neurotoxic.
• APP cut by y+b secretase -> release of AB -> AB helix monomer -> reorganises to B-sheet monomer -> combine with other monomers -> oligomers -> fibrils -> amyloid plaques.!! (learn this one)

Question 8

what change in APP occurs due to AD? why is this important?

Answer 8

• The transition from a-helix to beta sheet is important because it allows the monomers to compact down to form the oligomers which become the plaques.
• The oligomers are soluble to begin with, they reorganise into B-strands which group into protofilament -> collect together to form filaments -> collect to form an amyloid plaque.

Question 9

what is the role of tau in healthy people? [1]

what happens to tau in AD? (where / what / consequences) [3]

Answer 9

• Neurofibrillary tangles: hyperphosphorylatedtau forms the tangles - these are found in both the cell bodies and the dendrites.
• In healthy neurons, tau normally binds to and stabilizes microtubules.

In Alzheimer’s disease, however, abnormal chemical changes cause tau to detach from microtubules and stick to other tau molecules, forming threads that eventually join to form tangles inside neurons. These tangles block the neuron’s transport system, which harms the synaptic communication between neurons.

Question 11

what is tau depostion caused by?

what is the structure of the neurofibrillary tangles?

Answer 11

• Tau detaches from microtubule and aggregrates with other tau
• Causes neurofibrillary tangles: antiparallel B-sheet filaments
• The disintegration of the microtubule results in neuritic dystrophy

Question 12

what damage occurs to the brain bc of AD? [3]

where does it start / move to? [1]

Answer 12

• Brain shrinks
  
  • Gyri become narrower
  • Sulci become wider
  • Ventricles become larger
• Initially just in memory responsible part: entorhinal cortex and hippocampus. Moves to cerebral cortex - language, reasoning and social behaviour

Question 13

Beta-amyloid and tau activate which CNS cell?

Answer 13

• Beta-amyloid and tau activate microglia. Try to clear toxic proteins. Chronic inflammation occurs when microglia can’t keep up with all needs to be cleared

Question 14

what are the three cause of DS? explain them x

Answer 14

• Non-disjunction
  
  • Each cell has 3 copies of chromosome 21
  • Failure of homologous chromosomes (meiosis I) or sister chromatids (meiosis II) to separate properly in anaphase
• Robertsonian translocation DS
  
  • 3%
  • Chromosome 21 arm is translocated to chromosome 14 instead of being a separate chromosome 21
    
    • Zygote having: 21 21 14/21 14 = trisomy 21
• Mosaic DS
  
  • 2%
  • Combination of normal and trisomy 21 cells within individual tissues
    
    • Cell division takes place early in development after a normal egg and sperm unite

Question 15

what are characteristics of DS?

Answer 15

• A flattened face, especially the bridge of the nose
• Almond-shaped eyes that slant up
• A short neck
• Small ears
• A tongue that tends to stick out of the mouth
• Tiny white spots on the iris (colored part) of the eye
• Small hands and feet
• A single line across the palm of the hand (palmar crease)
• Small pinky fingers that sometimes curve toward the thumb
• Poor muscle tone or loose joints
• Shorter in height as children and adults

Question 16

what is the link between AD & DS?

Answer 16

• Similar genetic linkage:
  
  • Chromosome 21 contains APP (amyloid precursor protein)
    
    • Overexpression of APP in DS brain contributes to the high penetrance of early-onset Alzheimer disease commonly seen in DS patients.
• By 40, brains of almost all AD individuals with DS have significant levels of beta-amyloid plaques and tau tangles

Question 18

name 3 modifiable risk factors that increase risk of AD [3]

Answer 18

smoking, midlife obesity, a diet high in saturated fats, abstinence from alcohol in midlife, and consumption of >14 units of alcohol/per week have been associated with an increased risk for the development of AD.

Question 19

what inflammatory process is activated by AD? [3]

Answer 19

These oligomers and plaques cause an inflammatory process through microglial activation, cytokine formation, and activation of the complement cascade

Question 20

which genes code for APP? [2] what type of mutation causes early onset AD? [1]

Answer 20

The amyloid precursor protein and proteins from the presenilin 1 and presenilin 2 genes are involved in the formation of Abeta; missense mutations of these genes are responsible for most cases of early onset AD

Question 21

name two types of imaging might use to ID AD? [1]

Answer 21

PET /CT

(positron emission tomography / Computed tomography )

A combined PET/CT exam fuses images from a PET and CT scan together to provide detail on both the anatomy (from the CT scan) and function (from the PET scan) of organs and tissues

Question 22

what is the karyotype for

non-disjunction DS
Robertsonian translocation DS

Answer 22

non-disjunction DS: 47,XY / XX ,+21.

Robertsonian translocation DS: ​46,XY,rob(14;21),+21

Question 23

which structure does tau normally bind to ?

Answer 23

tau is a protein that interacts with tubulin to stabilize microtubules and promote tubulin assembly into microtubules