B15 APP

Question 1

Amyloidogenic Pathway

Answer 1

• APP cut by beta secretary
• > sAPPbeta
• Rest cut by Gamma secretase
• > Abeta->aggregates->pathology

Leftover :AICD

Question 2

Non-Amyloid Pathway

Answer 2

• alpha secretase cuts first
  = sAPPalpha
• followed by gamma secretase
  = p3 extracellular and AICD intracellularly

Question 3

Canonical View of App Parhways

Answer 3

• amyloidogenic Pathway ans non amyloidogenic Pathway
• these are mutually exclusive
• APP function unclear

Question 4

Amyloid Cascade Hupothesis

Answer 4

-missende Mutation in App/ PS1 or PS2 genes -> increased Abeta production and accumulation->Abeta oligomerisation Deposition as diffuse plaques-> subtle effects of Abeta oligomers on synapses-> microglia and astrocyte activation-> progressive synaptic and neurotic Injury -> progressive neuronal ionic homeostasis / oxidative injury ->altered kinase and phosphotase activities (branch of to tangle formation)-> widespread neural/ neuritic dysfunction and cell death with transmitter deficits =dementia

Question 5

Pros and Cons of amyloid cascade hypothesis

Answer 5

Pro:

• aBeta toxic to Neurons
• FAD mutations in mice = amyloid pathology and cognitive deficits
• FAD mutations alter APP metabolism
• trisomy 21 causes AD pathology (chromosome 21 coding APP)
• Tau gene mutations cause dementia but not AD
• Beta cleavage reducing mutations are protective against AD (Icelandic )

CON:

• Abeta Plaques can be found in healthies
• Abeta levels do not correlate with cognitive impairment
• FAD mutations in mice show amyloid deposition but no neuronal loss
• inactivation of presenilin cause synaptic dysfunction and memory impairment (part of gamma secretase mechanism)
• presenilin mutations found in familiar FrontoTemporallobe dementia with no amyloid deposition

Question 6

Alpha Secretase

Adams Family

Answer 6

Adam stands for : a disintegrin and metalloprotease

• metalliprotease and membrane proteins expressed in brain (appropriate place for alpha cleavage)
• ADAM 9,10, 17
• of overexpressed increased sAPPalpha generation
• knock down =decease in sAPPalpha generation
• expressed on cell surface and late transgolginetwork - where cleavage happens

Question 7

Beta secretase -

It’s all about the BACE

Answer 7

• membrane protein
• needs to be cleaves to be activated
• expresses in Neurons but not glia (appropriate place for beta cleavage)
• overexpressjon =increase in Abeta and sAPPbeta
• knockdown= preventing generation of Abeta and aAPPbeta
• BACE1 only active at acidic ph -> can only do beta cleavage in endpapers and TGN

Question 8

Gamma secretase

Answer 8

Multiprotein Complex

1. Nicrastin: required for stability and assembly - binds to-
2. APH1: also stability and assembly
3. Presenilin: contains catalytic aspartic acid resedue -> binds bit is not active
4. Pen-2: binds gamma secretase complex and activated by cleaving PS1

Nibbling: depending on how long substrate remains bound to enzyme the secretase will keep cutting chunks of amino acids which results in different lengths of Abeta (relevant for developing AD)

-initial cleavage creates amyloid intrazellulär Domain +aBera residue