Neuroinflammation in Alzheimer's Disease- Freitag

Question 1

Amyloid ß (Aß) plaques are produced due to…

a. Aß aggregation
b. Tau hyper-phosphorylation
c. both Aß aggregation and Tau hyper-phosphorylation
d. Tau accumulation
e. synaptic damage that leads to over-activation of scaffold proteins

Answer 1

c. both Aß aggregation and Tau hyper-phosphorylation

Question 2

according to the amyloid hypothesis, plaque formation is due to…
a. physiologically formed Aß oligomers are cut into Aß monomers by alpha-secretase. these monomers float around the cell and bind to membrane proteins and accumulate at synaptic sytes

b. oligomerisation of Aß monomers due to false breakage of APP molecules. results in formation of long fragmented fibrils and plaque formation
c. mutation in Aß monomers lead to clustering of these monomers and formation of oligomers
d. none of the above

Answer 2

b. oligomerisation of Aß monomers due to false breakage of APP molecules. results in formation of long fragmented fibrils and plaque formation

Question 3

according to the tau hypothesis, plaque formation is due to…
a. mutation in tau protein leads to hyper-phosphorylation of tau and aggregation into tau fibrils and the formation of neurofibrillary tangles

b. over-production of the enzyme tau-phosphatase leads to hyper-phosphorylation of tau, aggregation of these into fibrils and the formation of neurofibrillary tangles
c. aggregation of phosphorylated tau and Aß-oligomers
d. b and c are correct

Answer 3

a. mutation in tau protein leads to hyper-phosphorylation of tau and aggregation into tau fibrils and the formation of neurofibrillary tangles

Question 4

how does AD differ from other neuroinflammatory (NI) diseases?
a. all NI diseases are caused by a pathogen whereas AD is caused by an autoimmune response

b. in NI-diseases there is a mutation in CD4-T cells which results in inflammatory response in the brain whereas the inflammation in AD is caused by B-cells
c. in NI-diseases there is invasion of cells of the adaptive immune system into the CNS whereas in AD it is a problem of the innate immune system and activation of CNS-resident immune cells
d. NI-diseases are very variable and therefore it is unknown how AD differs from other diseases with respect to inflammation

Answer 4

c. in NI-diseases there is invasion of cells of the adaptive immune system into the CNS whereas in AD it is a problem of the innate immune system and activation of CNS-resident immune cells

Question 5

which of the following statements is/are correct?
a. in AD, there is an imbalance between pro- and anti-inflammatory cytokines due to upregulation of pro-inflammatory cytokines (IL-16, IL-12…) and downregulation of anti-inclammotory cytokines (IL-10, TGF ß)

b. in AD, both pro- and anti-inflammatory cytokines are upregulated (IL-16, TNF-alpha, IL-10…) some cytokines such as TGF ß (anti-inflammatory) are downregulated
c. in AD, cytokines such as IL-16 are upregulated
d. IL-4 and IL-23 are both anti-inflammatory cytokines which are downregulated in AD

Answer 5

b and c:

b- in AD, both pro- and anti-inflammatory cytokines are upregulated (IL-16, TNF-alpha, IL-10…) some cytokines such as TGF ß (anti-inflammatory) are downregulated

c- in AD, cytokines such as IL-16 are upregulated

Question 6

how do microglia promote inflammation in AD? (more than 1 answer might be correct)

a. Aß oligomers interact with MG via receptor mediated interaction and activate them
b. Aß oligomers interact with MG via non-receptor mediated interaction which results in primed MG
c. fibrils of Aß oligomers activate primed MG fully via receptor mediated interaction
d. both Aß oligomers and fibrils are toxic for MG

Answer 6

b, c, d:

b- Aß oligomers interact with MG via non-receptor mediated interaction which results in primed MG
c- fibrils of Aß oligomers activate primed MG fully via receptor mediated interaction
d- both Aß oligomers and fibrils are toxic for MG

Aß oligomers prime MG and reduce their phagocytic capacity (less clearance of Aß oligom), and the fibrils activate them completely which results in release of cytokines and inflammation

Question 7

which cell types are involved in neuroinflammation in AD?

Answer 7

• MG
• Astrocytes
• myeloid cells
• other CNS cells (neurons, oligodendrocytes, endothelial cells)

Question 8

what is the role of astrocytes in neuroinflammation/AD?

Answer 8

undergo atrophy due to release of pro-inflammatory cytokines from MG–> this activation proceeds the Aß-plaque related astrogliosis, which impairs glutamate transmission (lack of glu clearence or reduced glu relaese) and leads to cognitive deficits and excitotoxicity

Question 9

how can one analyse cytokines and glial cells?

Answer 9

• assays (ELISA, western blot, RT-qPCR)
• separation of cell types (MACS- with CDII-6 beads for MG and ACSA beads for astrocytes)
• co-culture systems