Week 9.2 Flashcards
Misfolding pathway to Amyloid fibres And Cell Toxicity
What affects Ab?
Misfolding pathway to Amyloid fibres And Cell Toxicity
Anything that alters the kinetics or thermodynamics of the Ab forms will influence the disease
Ab
neuro-toxicity
Ab causes AD
but in what form?
small oligomer or mature fiber
Ab Oligomer
correlated with synaptoxicty and memory loss not plaques
What particular ‘mer’ how many kDa is it?
What does Ab 56 correlate with?
•Small oligomers in particular a 12 mer of Ab ; 56 kDa
•
•Concentration of Ab*56 correlated with memory loss and synaptic function (but does not cause cell death)
•
•early memory loss - not correlate or amyloids or Neurofibralar tangles or cell death
** Ab oligomers are most toxic? **
Does the concentration of amloids correlate with progression of disease?
What do animal models show about APP?
The conc of amyloids does not directly correlate with progression of disease
Animal models with elevated APP show neuronal abnormalities before fibrils can be observed
Non_fibrillar oligomeric forms of Ab cause cell death
Mature amyloids could represent inactive reservoirs of Ab in equilibrium with neurotoxic assemblies. Plaques show Cell death in close proximity
**What are the Mechanism of Ab toxicity? **
Whare are the two hypothesis?
Mechanism of Ab toxicity (We do not know**) **
There are a number of hypothesis:
- *1)Membrane Disruption may be cause of Ab toxicity outside the cell (or possibly inside)
2) Direct interaction with a membrane receptor**
Mechanisms of toxicity?
Pore like structures of annalar protofibrils?
**Pore like structures of Annalar protofibrils to cause membrane permeability- ion channels and cell death **
Annular Protofibril pores may be responsible for neuronal death not mature fibrils
Intracellular Ab toxicity?
Although Ab plaques form outside cell
Most Ab first generted inside vesicals (lumen) within the cell
Toxic action could be inside cell?
Ab oligomer interaction with membrane surface receptors, in particular:
- *-NMDAR
- AMPAR
- mGluR**
- PrPC
The prion protein confers Ab neuro-toxicity
What does the prion protein do?
NMR can map Ab oligomer recognition site
Nature paper: Cellular prion protein mediates impairment of synaptic plasticity by amyloid-B oligomers (It is saying that Ab oligomer toxicity is dependent on the presence of PrPc)
Prion Protein inhibits Ab fibre formation
when you add the two together you should get fibres forming? ^^^
expected to see fibre growth to increase rapidly – but it didn’t at all, but you do have oligomers
Prion protein has high affinity for Ab and has profound influence for pathway for fiber and traps it in toxic oligomeric state
NMR can map Ab oligomer recognition site
We can see where it binds
Ab monomer doesn’t recognise the prion protein but as Ab changes there is a different binding surface – develops strong high affinity for Ab
Copper2+ and Alzheimer’s (not universally excepted)
What is the neuro-toxicity of Ab linked to?
What does Cu2 induce?
What does Cu2-Ab generate?
Copper2+ and Alzheimer’s (not universally excepted)
COPPER DOES NOT CAUSE AD NOT THE MOST IMPORTANT THING DESPITE THE FACT THE VILES LOVES IT
Copper2+ and Alzheimer’s
(not universally excepted)
Neuro-toxicity of Ab linked to ROS (H2O2)
Cu(II) found bound to amyloid beta within plaques
Cu(II) will induce more rapid fibre formation
Cu(II)-Ab will generate free radicals (ROS) - diffusible oligomer of Ab will concentrate Cu(II) at neurons
Copper generated Ab proto-fibrils disrupt membranes
What is the workflow for this?
Impaired Copper and ROS homeostasis
V
Up-regulation of Ab as an antioxidant
V
Ab oligomers & deposits
V
Ab oligomers concentrate redox active copper at the neuronal membrane
V
Altered neuronal ionic homeostasis and oxidative injury
V
Altered kinase/phosphatase activities leading to tangles
V
Neuronal Cell Death
Unanswered questions
Precise nature of toxic form of Ab ?
Site of toxicity ?
Mechanism of toxicity ?
Treatment of AD
How will our understanding of AD informed drug design?
Present Treatments
What can we treat?
What are current drugs used for?
•At present we can only treat the symptoms not the cause
•
•inhibit the enzyme acetyl-cholinesterase so as to raise acetylcholine levels
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•behavioural drugs for mood swings
Approaches to developing Therapeutics
six broad approaches
1) inhibit b and g secretases
Need an inhibitor of an aspartyl protease that can pass blood/brain barrier, for the g secretases need a membrane associated inhibitor
2) prevent Ab oligomerization
might be counter productive!
or promote clearance
Ab by immunization creates anti-bodies then get microglial clearance
•3) anti-inflammatories
Ab accumulation promotes inflammation eg ibuprofen
•
•4) cholesterol homeostasis
Lower cholestrol a risk factor eg statins are well tolerated
•
•5)Cu/Zn metal ion chelation
Cu chelator clioquinol can pass the blood brain barrier
•6) antioxidants
cell death is linked with oxidative damage, however so far antioxidants have been ineffective
Summary
- AD is 4th biggest killer in the West
- AD is characterised by deposits of extra-cellular amyloid plaques
- The amyloid fibrils found in senile plaques are principally composed of amyloid-b-peptide (Ab).
- Amyloid fibrils contain an ordered arrangement of b-sheet folded Ab peptides-Cross beta motif
- Ab is produced via the post transitional processing of APP
- Early onset familial-AD is caused by increased production and/or deposition of Ab in the brain.
- Ab accumulation causes oxidative injury causing altered phosphatase activities leading to neurofibrillar tangles of tau protein and finally dementia.
