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Flashcards in ND - L3 Deck (20):
1

Neuropathology of AD

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

2

What aspects of amyloid beta peptide aggregation were discussed?

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

3

Amyloid plaques

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

4

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

oligomers

5

Generation of Abeta

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

6

Genetics of Abeta

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

7

Cleavage of Abeta

BACE then gamma secretase

8

APP

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

9

Turnover of amyloid

rapidly formed and degraded (8% every 36hrs)
degraded by IDE, Neprilysin, MMPs, angiotensin CE

10

Neurofibrillary tangles

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

11

Normal tau function?

attached to microtubules

12

Abnormal tau function?

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

13

Describe the ROS pathway

-

14

Oxidative stress

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

15

What are the consequences of oxidative stress?

lipid peroxiation, protein oxidation, DNA oxidation

16

Biometals

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

17

What does copper do to neuropathology?

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

18

Neuroinflammation sources

activated microglia, peripheral monocytes

19

Neuroinflammation initiation

aggregated amyloid, degenerating synapses & neurons

20

Neuroinflammation consequences

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