Alzheimer's disease

Question 1

Symptoms of AD?

Answer 1

• day-to-day memory – e.g. difficulty recalling events that happened recently,
• concentrating, planning or organising – e.g. difficulties making decisions,
  solving problems or carrying out a sequence of tasks (such as cooking a
  meal),
• language – e.g. difficulties following a conversation or finding the right word
  for something,
• visuospatial skills – e.g. problems judging distances (such as on stairs) and
  seeing objects in three dimensions,
• orientation – e.g. losing track of the day or date, or becoming confused
  about where they are.

Question 2

What are the mutations in familial AD?

Answer 2

APP (increase AB 1-40 and AB1-42)
PSEN1
PSEN2

Psen increase ratio of AB 1-42: 1-40

Question 3

How many a.a in APP

Answer 3

695

Question 4

What role does immune response play in AD

Answer 4

Immune response is NOT necessarily damaging inflammation.
The microglia cluster around plaques

TREM2- anti-inflammatory response

Question 5

Advantage of WGCNA microarray or RNAseq

Answer 5

Correlation very high 0.97 for association of genes like C1qa and Trem2 with plaques

Question 6

**What is the knock in model of AD

Answer 6

Ab knock in APP knock-ins (Swedish; Beyreuthian + Arctic)
(Saito and Saido, Riken Japan)

Tau knock in mice (normal human or mutated)

Question 7

What is the difference between transgenic Vs knock in model of AD*

Answer 7

Transgenic models- issues with overexpression of mutation
Cheaper and use older mice

knock in **

Question 8

What is the hypothesised role of TREM2

Answer 8

Anti-inflammatory, removing damaged synapses.

Question 9

What is the issue mouse models of AD right now?

Answer 9

Mice do not naturally form dementia so knockin of AB will not create tau and the amyloid cascade effects.

It may because mice have a stronger immune system so their plaque build up would be mitigated

Question 10

What do mouse amyloid models currently show?

Answer 10

Increased glutaamte
Depositon of plaques with local synapse loss
-Subtle behavioural changes

Question 11

What do the current tau models show?

Answer 11

Loss of synapses
cell death
loss of brain tissue
-Cognitive impairment

Question 12

What are the research questions surrounding AD modelling?

Answer 12

1.Effects of different forms of Aβ?
2.What are the first effects of Aβ?
3.whats special about age
4. What do microglial genes do
5. Why don’t plaques cause tangles in mice

Question 13

Describe the two knock in mouse models of AD

Answer 13

1. App NL-F (Swedish & Iberian)
   Increases Ab 1-42 levels
   Develop plaques at ~9 months
2. APP NL-GL-F (Swedish & Iberian & arctic)
   Increases Ab oligomers
   Plaques at ~2 months

Question 15

Paired pulse ratio ?

Answer 15

Paired pulse ratio inversely proportional to release probability which means soluble plaques causes glutamate release presynaptically before plaques even forms.

Question 16

What happens to LTP

Answer 16

Level unchanged but mechanism altered

Question 17

What have been the improvements in creating mouse models?

Answer 17

Adding human risk factors e.g. obesity/disbetes

Question 18

What did spatial transcriptomics (wood study) reveal about plaques and microglia?

Answer 18

Wood et al. use spatial gene expression
analysis to assess the effect of microglia
plaque contact in aged App knockin
mice. Genes in a pathway from Trem2,
complement factors, phagocytosis, and
lysosomal degradation have increased
expression in microglia on plaques;
increased expression is prevented with
human GWAS risk mutation Trem2R47H.

Question 19

Summary hypotehsis for AD

Answer 19

Long-term Abeta-induced hyperactivity →excess Ca2+ influx →mitochondrial
damage →Tau tangles and neurodegeneration, leading to cognitive decline