Innate immunity in neurodegenerative diseases

Question 1

Mention a neurodegenerative disease with innate immunity involvement.

Answer 1

Alzheimer’s

Question 2

Describe Alzheimer’s disease.

Answer 2

Degenerative cerebral disease:
- generel shrinkage of brain
- amyloid-beta plauqes
- phospho tau tangles
- bigger microglia
- reduced metabolism

Question 3

What is a symptom of Alzheimer’s?

Answer 3

Dementia

Question 4

What is the problem with AD?

Answer 4

It’s usually first diagnosed after the optimal therapeutic window

Question 5

What are some of the risk factor genes for AD (prioritized)?

Answer 5

• APP (amyloid precursor protein) metabolism genes
• cholesterole genes
• immune response genes

Question 6

What is the main risk factor for AD?

Answer 6

Age

Question 7

What are the two main types of AD, and how do the differ?

Answer 7

EOAD or (early) Familial AD
- < 3 %
- (gain of function) mutations in the APP or presenilin 1/2 genes –> overproduction of A-beta
- rapid course

LOAD or Sporadic AD
- > 97 %
- ApoE genotype –> reduced A-beta clearance
- other genes: innate immunity, endosomal recycling, lipid transport, SNPs
- less rapid course

Question 8

Describe the APP processing via the non-amyloidgeneic pathway.

Answer 8

APP -(alfa-secretase)-> C83 (intracellular) + sAPP-alpha (extracellular) -(gamma-secretase)-> p3 (extracellular) + AICD (intrecellular)

Question 9

Describe the APP processing via the amyloidgeneic pathway.

Answer 9

APP -(BACE-1)-> sAPP-beta (extra) + C99 (intra) -(gamma-secretase)-> A-beta (extra) + AICD (intra)

Question 10

What are A-beta oligomers involved in?

Answer 10

A number of cellular responses, e.g., cell cycle reentry, ChAT loss, insulin resistance and plasticity dysfunction

Question 11

What are the normal function of Tau?

Answer 11

Involved in axonal transport

Question 12

What are the pathological function of hyperphosphorylated tau?

Answer 12

Disruption of axonal transport

Question 13

Describe how ApoE is involved in A-beta clearance.

Answer 13

Apo-E lipoprotein (Apo-E + cholesterole) –> Apo-E and A-beta complex –> microglia phogocytosis ?

Question 14

What other mechanisms of A-beta clearance are there?

Answer 14

• interstitial fluid drainage
• uptake by astroglia and neurons
• uptake by brain microglia

Question 15

What are some high risk factor genes for sporadic AD?

Answer 15

ApeE and TREM2
Both involved in A-beta clearance

Question 16

How does AD affect microglial function?

Answer 16

Chronic inflammation –> continuosly activated microglia (disease associated microglia: big)