ND - L3

Question 1

Neuropathology of AD

Answer 1

gross atrophy of the brain
amyloid plaques
intraneuronal neurofibrillary tangles
activation of microglia, hypertrophy of astrocytes
dementia (correlates with loss of synapses)
loss of neurons
enlarged ventricles

Question 2

What aspects of amyloid beta peptide aggregation were discussed?

Answer 2

amyloid plaques
amyloid formations
generation of Abeta
genetics of AD & amyloid
cleavage of Abeta
APP
turnover of amyloid

Question 3

Amyloid plaques

Answer 3

aggregated Abeta peptide (forming fibrils)
green-red birefringence with red congo stain (describe)
high concentrations of metal ions
associated with secondary inflammation

Question 4

Describe amyloid formation pathway. Which element is thought to be the primary toxin?

Answer 4

oligomers

Question 5

Generation of Abeta

Answer 5

cleaved form APP by secretases (describe a,b g)
cleavage occurs at membrane & release to extra
deposits between cells

Question 6

Genetics of Abeta

Answer 6

familial AD (5%) - mutation in APP, PS1 or PS2
late onset AD - ApoE4, risk factor genes (PICALM, CD33, TREM2, EPHA1)

Question 7

Cleavage of Abeta

Answer 7

BACE then gamma secretase

Question 8

APP

Answer 8

ch 21 (down syndrome)
GF-like domain, protease inhibitor domain, metal binding domain
extensive post-translational processing

Question 9

Turnover of amyloid

Answer 9

rapidly formed and degraded (8% every 36hrs)

degraded by IDE, Neprilysin, MMPs, angiotensin CE

Question 10

Neurofibrillary tangles

Answer 10

paired helical filaments
protein aggregates within neurons
composed of hyperphosphorylated tau (makes insoluble and aggregates)

Question 11

Normal tau function?

Answer 11

attached to microtubules

Question 12

Abnormal tau function?

Answer 12

released from microtubules, inhibition of intracellular transport –> increased oxidative stress –> cross-linking –> inhibits degradation of NFTs

Question 13

Describe the ROS pathway

Answer 13

-

Question 14

Oxidative stress

Answer 14

leakage of molecular intermediates from mitochondrial ETC
metals can catalyse free radicals
inflammation

Question 15

What are the consequences of oxidative stress?

Answer 15

lipid peroxiation, protein oxidation, DNA oxidation

Question 16

Biometals

Answer 16

zinc & copper (despite high Al)
increased extra, decreased intra
bind Abeta at His & Tyr –> promotes aggregation
metals excreted by neurons trapped

Question 17

What does copper do to neuropathology?

Answer 17

neurotoxic oligomers

cross-linking b/w Abeta monomers –> neurotoxic dimers

Question 18

Neuroinflammation sources

Answer 18

activated microglia, peripheral monocytes

Question 19

Neuroinflammation initiation

Answer 19

aggregated amyloid, degenerating synapses & neurons

Question 20

Neuroinflammation consequences

Answer 20

neurotoxic cytokines, increased free radicals, damage (also can be beneficial, clears amyloid)