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