Hampel et al 2021

Question 1

Describe the progression of Abeta and its relation to clinical progression.

Answer 1

Abeta spreads throughout the cortex in the preclinical stages (10yrs before)
Then regions like EC and CA1 also have Abeta depositions in early AD
Eventually reaches brainstem and cerebellum during clinical AD

Question 2

Describe the differences between EOAD and LOAD.

Answer 2

EOAD is familial AD and is caused by increased production of Abeta
LOAD is sporadic AD and caused by decreased proteostasis and clearance of Abeta

Question 3

How does mutation in APP affect AD? Are there protective forms?

Answer 3

Mutations can increase affinity to beta secretase and thus favor amyloidogenesis
Mutations can be protective by decreasing affinity instead

Question 4

How does mutation in PSEN affect AD?

Answer 4

Part of the gamma secretase complex -> can increase abeta42 cleavage (less soluble and more potent to aggregate)
Can impair ELN by decreasing lysosomal function

Question 5

How does ApoE4 affect AD and onset?

Answer 5

It shifts the onset of Abeta deposition and cognitive impairment.

Question 6

How does ApoE4 affect Abeta metabolism?

Answer 6

Can increase gamma secretase activity, APP transcription, and Abeta seeding

Question 7

Give 2 examples of ApoE protective variants.

Answer 7

ApoE3ch variant
- Has extensive abeta accumulation but limited tau spreading
- delays onset by decades
- protect against familial AD

ApoE2
- delay onset by decade
- decreases pathological burden (abeta seeding and clearance)

Question 8

How do epigenetics affect Abeta pathology?

Answer 8

APP CpG methylation can block transcription. This is decreased in the AD brain

Abeta glycation important for aggregation

Question 9

Physiological role of APP? (3)

Answer 9

APPsalpha involved in spine remodeling
APPsalpha can impact synaptic plasticity by binding GABAR
APP can bind intracellur GABAR subunit to promote trafficking to synapse

Question 10

Physiological role of Abeta? (2)

Answer 10

Synaptic vesicle trafficiking
Trigger BDNF transcription via CREB -> HPC neurogenesis

Question 11

Why does Ab42 aggregate more than 40?

Answer 11

Decreased solubility
Also glycation can increase protease resistance and decrease solubility
Increased stability at low pH -> withstand lysosome

Question 12

Describe how soluble Ab oligomers can affect dendritic spine.

Answer 12

Can reduce NMDAR and AMPAR expression and thus reduce LTP and spine density

Question 13

Describe how microglia and protofibrils interact.

Answer 13

Microglia can internalize these and accumulate
Then can release through microvesicles to spread
Abeta can withstand lysosomal degradation and can also lead to IL-1Beta release from microglia

Question 14

What is the arctic Swe mouse model?

Answer 14

Protofibril model and only has intraneuronal protofibril accumulation without plaques -> cognitive deficits

Question 15

How do abeta fibrils and plaques contribute to AD?

Answer 15

Causes synaptic dysfunction but more so catalyzes assembly of soluble Abeta to contribute to toxicity

Question 16

Describe how Abeta can influence tau pathology?

Answer 16

Abeta accumulation can trigger or facilitate tauopathy by increasing phosphorylation through GSK3beta and Cdk5
If Abeta is below clinical threshold, tau does not spread beyond MTL

Question 17

Provide examples of how Abeta and tau synergize in mice

Answer 17

Abeta injected into tau tg mice can exacerbate tau aggregation
When decreased tau seeding, it rescues neurodeg and memory deficits

Question 18

What are ways microglia combat AD? What are two ways it can interact with Abeta?

Answer 18

It creates a physical barrier surrounding plaques to prevent spreading
Abeta interaction through
1) phagocytosis
- TREM2 is a positive regulator
2) surface receptors (CDs and TLRs)
- Promote ILs and TNFalpha -> proinflammatory
- Decrease anti-inflammatory cytokines TGFbeta

Question 19

How do astrocytes react to Abeta?

Answer 19

Can phagocytose or release ILs and cytokines during reactive astrocytes

Question 20

How does Abeta affect the cholinergic system? What brain regions?

Answer 20

Basal forebrain has cholinergic output to other cortical areas
One of the first sites to degenerate in AD
Abeta accumulation correlates well with degeneration here

Question 21

Why is acetylcholine important for preventing AD? (2)

Answer 21

1) M1 receptor agonist and can promote alpha secretase pathway
2) nicotinic receptor agonist and can decrease GSK3beta activity

Question 22

How is glutamate involved in AD? What are the specific ways? (3)

Answer 22

Glutamate excitotoxicity via tonically open NMDAR
1) generate toxic radicals
2) release apoptotic factors
3) impair LTP because indistinguishable from actual synaptic input

Question 23

Describe how Abeta promotes NMDAR and AMPAR dysregulation.

Answer 23

First enhances NMDAR activation and inhibit glutamate uptake
Prolonged exposure can decrease NMDAR and AMPAR expression -> decrease spine density and plasticity