Alzheimer’s Flashcards
Pathology:
o Amyloid beta plaques
o Location of plaques
Intracellular (specifically the mitochondria)
Extracellular
o Neurofibrillary tangles – composed of protein called Tau found deep within the cell
Most significant risk factor:
age
Two types of Alzheimer’s disease:
Early onset
- pre-65y (1-5% of cases)
- Mutations in genes encoding:
- Amyloid precursor protein (APP) (large protein produced in the brain which is chopped up into smaller fragments by enzyme activity one of them being amyloid beta. )
- Presenilin 1 (component of γ-secretase)
- Presenilin 2 (component of γ-secretase)
- Affects production of Amyloid-β (Aβ1-42)
- Mutations of these affect production of amyloid beta
Late onset
- Unknown cause
- Genetic cause?
- E.g. apolipoprotein E (ApoE)
- Produced by the astrocytes
- Function of ApoE – transport cholesterol into neurones
- Thought that ApoE binds AB – regulated aggregation leading to inflammation of the brain
- ApoE 4 form = mutation in gene – less effective in regulating aggregation = risk factor
Amyloid hypothesis:
Amyloid precursor protein (AAP) is processed to a smaller protein AB –which accumulated as plaques in the brain leading to AD?
Evidence:
- APP gene – chromosome 21
- Downs syndrome (trisomy 21) – extra chromosome, extra gene, produce more AAP
- Invariably exhibit AD characteristics by 40 years old
APP processing:
- APP embedded in the membrane
- What usually happens is APP is cut by an alpha secretase and gamma secretase
- Releases fragments which we use in the brain which helps with function of the synapse and learning and memory
- When this a secretase cuts soluble app is released (normal process happening all the time in our brains)
- When APP is cut by b secretase, leads to amyloid beta (42 version) very poor in terms of solubility and these starts to clump together in brain
- When B secretase and y secretase cut and process the APP, they produce AB insoluble peptide 42 mer
- Another fragment also produced (N APP) which binds to Neurone death receptor 6 and can lead to death as a consequence.
Consequences of amyloid insoluble plaques:
Synapse disruption and cell death
Tau hypothesis:
- Microtubules: scaffolding and transport system (nutrients, molecules)
- They are a transport system within the cell
- Microtubules act as motorways trafficking components around the cell
- Phosphorylation: adding a phosphate group to a protein
- Phosphorylation of tau stabilised microtubules
- Problem is, when tau is hyperphosphorylated, microtubules start to disintergrate leading to neurofibrillary tangles
- Unable to move compounds through the cells and they start to die.
Areas affected in Alzheimers:
- Hippocampus
• New memory formation
• Cf memory retrieval - Amygdala
• Emotional recall - Cortex
• Memories from longer ago are lost
Ischemic stroke:
- More common
- Disrupted blood supply to the brain (could be due to various things)
- Clot, plaque
Addressing condition: lifestyle diet, exercise, statins
Treatment is extremely limited:
- Tissue plasminogen activator (Alteplase) –> thrombolytic effect
- NICE guidelines – 4.5 hours
Haemorrhagic stroke:
• Bleeding into the brain • Surgery - craniotomy – Remove clot – Repair burst blood vessels – Blood pressure (ACE inhibitors, beta-blockers), lifestyle, exercise…..
Stroke areas:
In a stroke:
- Cells deprived of nutrients and O2
- Cell death and brain damage
Two areas to stroke:
o Inner area: Umbra – so much damaged that tissue cannot be repaired
o Penumbra: around the core of the stroke there is potential for recovery
Aims of treating a stroke?
After stroke, cytokine interleukin 1 beta produced, Interleukin 1 binds to IL1 receptor, this tells cells to produce more IL6 sand TNF, this exacerbates damage due to more release of inflammatory cytokines = more inflammation and cell death
-Want to block this inflammation
Anakinra = IL1 receptor antagonist, therefore, you reduce production of inflammatory cytokines and reduce the damage
