AD - Amyloid Flashcards
What is the function of APP?
Unknown
Thought to be involved in cell adhesion, neurite growth and synaptogenesis though
What are the major and minor pathways APP processing?
Major - cleaved into harmless fragments
Minor - cleaved into amyloid beta
What cleaves APP and where?
Alpha secretase between point 16 and 17
What is the known protective variant of APP?
A673T
What is the known pathological mutation of APP?
A673V
Where is the APP gene found?
Chromosome 21
Which other condition is AD strongly associated with?
Down Syndrome
What is amyloid beta
A product of the cleavage of APP
39-42 peptides long
What is the relationship between length of Ab and rate of disease?
Longer length = faster rate (generally)
How do amyloid plaques form?
Monomers > oligomers > fibrils > diffuse plaques > amyloid plaques
Which variant of Ab is most commonly found in plaques?
Ab42
Which two variants of Ab form strong bonds between ionised side chains to form plaques?
42 and 43
What occurs first: neurodegeneration or plaques?
Mouse models show neurodegen before plaque formation
Does Ab induce apoptosis?
Well yes in cultered cells and post mortem brain tissue
But not in transgenic mice
Does Ab cause oxidative damage?
Yes through the increase of ROS production
What has been shown to be protective against Ab-induced-oxidative damage?
Antioxidant E and oestrogen
What is Ab thought to do, but we are unsure?
Promote aggregation of Tau to form tangles
Insert into cellular membranes to disrupt integrity
Why do we think that Ab plays a role in AD?
People diagnosed with AD have many more plaques in the brain than those without
Genetic mutations seen in AD also seem to cause increase Ab
Transgenic mice expression mutant human APP develop plaques and neurodegen
Aggregates Ab toxic to cells in culture and rhesus monkey brain. This would produce the clinical features of AD
Outline the amyloid hypothesis.
APP broken down by a series of secretases
During this an insoluble Ab-42 accumulates and is deposited extracellularly
“Sticks” to this and other protein fragments like ApoE4 to form plaques
Which genes are responsible for gamma secretases?
PSEN1 PSEN2
Why are PSEN genes relevant to AD?
They are responsible for gamma secretases which cleave to form Ab
