Alzheimer's disease Flashcards
Main risk factor for Alzheier’s
Age (65+)
`Leading causes of death in the UK
research investment
Nov 2016 – ONS announces AD & d
Clnical symptoms of AD
Memory loss – especially recently acquired information
Disorientation/ confusion – forgetting where they are
Language problems – stopping in the middle of a conversation
Personality changes – becoming confused, fearful, anxious
Poor judgement – such as when dealing with money
What is the genetics assocated with AD
APP, PSEN, (both increase early onset alzeimers)
ApoE (hereditary ~ 8%) … more prevalent, increases likelihood of late stage alzheimers disease
Outline the amyloid hypothesis - physiological hypothesis
On the plasma membrane
Amyloid preceutor protein (APP) cleaved by a-secretase
sAPPa released - C83 fragment remains
C83 is digested by gamma-secretase
Products removed
What is the amyloid hypothesis- Pathophysiological processing
just clarify here this happens
APP cleaved by b-secretase
sAPPb released - C99 fragment remains
C99 gets digested by gamma-secretase releasing b-amyloid (Ab) protein
Ab forms toxic aggregates (extracellular)
Outline the Tau hypothesis - physiology
Soluble protein present in axons
Important for assembly & stability of microtubules
Outline tau protein pathophysiology
Hyperphosphorylated tau is insoluble leads to self-aggregates to form neurofibrillary tangles
These are neurotoxic
This also results in microtubule instability
INTRACELLULAR
What happens to the Ab proteins produced in amyloid hypothesis
They are monomers that can dimerise, trimerirse etc.
this forms plaques which likely leads to cell death
Physiology of inflammation hypothesis- physiology
Specialised CNS immune cells - similar to macrophages
Pathophysiology of inflammation hypothesis
Pathophysiology - Microglia
Increased release of inflammatory mediators & cytotoxic proteins
Increased phagocytosis
Reduced levels of neuroprotective proteins
What would you expect of someone taking ibuprufen in terms of likelihood to develo alzheimers
Less likely maybe because of less inflammation
Drug types for amzheimers
Anticholinesterases
NMDA receptor blocker
List the anticholinesterases
- Donepezil
- Rivastigmine
- Galantamine
What is the mechanism of donepezil action
Anticholinesterase
Reversible cholinesterase inhibitor.
Long plasma half-life
Stark symptom improvement but only for a year
What is the mechanism of rivastigmine
Pseudo-reversible AChE & BChE inhibitor… inhibits BOTH isoforms (but don’t want to inhibit BChE)
8 hour half-life (not as long as donepezil)
Reformulated as transdermal patch
Outline the mechanism of actin of galantamine
Reversible cholinesterase inhibitor
7-8 hour half-life
a7 nAChR agonist (partial agonist of neuronal nAChR, not muscle type)
so inhibitio of cholinesterase and also partial agonist
List a NMDA receptor blocker
Memantine
What is the mechanism of action of memantamine
Use-dependent non-competitive NMDA receptor blocker with low channel affinity
Moderate-severe AD
Long plasma half life
Why is NMDA receptor blocker usefull in AD
Because in neurodegeneratin there seems to be increased glutatmate activty (and reduced GABA
So only effective in LATE STAGE disease (because neurodegeneration only causes suffiecient glutamate to for NMDA activation to cause symptoms)
last slide won’t appear in exam
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