Alzheimer's Disease Flashcards
what is the main risk factor for alzheimers’ ?
age >65
What are clinical symptoms of alzheimers’ ?
- 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
Genetic inheritance of alzheimer’s (~8%)
- APP
- PSEN
- ApoE
-
describe the amyloid hypothesis
in normal physiology
- cell memb of neuronal cells
- -> gamma sec, alpha sec, APP
- a secretes cleaves APP
- sAPPalpha = released
- -> C83 fragment remains - C83 = digested by gamma secretes
- products are removed
describe the amyloid hypothesis
in pathological physiology
- b-secretase cleaves APP
- sAPPbeta = released
- -> C99 fragment remains - C99 = digested by gamma-secretase –> releasing Beta-Amyloid (AB) protein
- AB forms toxic aggregates
describe the Tau hypothesis
(normal physiology)
+
(Pathophysiology)
(Normal Physiology)
- soluble (tau) protein = present in axons
- -> which is important for assembly and stability of microtubules
(Pathophysiology)
1. Tau protein = hypoerphosphorylated –> becomes insoluble
2. then self aggregates to form neurofibrillary tangles
–> aggregates = intracellular
+ neurotoxic
3. results in microtubule instability
Describe the Inflammation hypothesis
(normal physiology)
+
(Pathophysiology)
(normal physiology)
- Specialised CNS immune cells = similar to macrophages
(Pathophysiology)
- there is increase in release of inflammation mediators + cytotoxic proteins
- causes increase in phagocytosis
- decrease in level of neuroprotective proteins
What are 4 drugs licensed to treat alzheimers?
Anticholinesterases: (usually early stage AD)
- Donepezil
- Rivastigmine
- Galantamine
NMDA receptor blocker: (usually late stage AD)
- Memantine
How do Donepezil act as treatment for Alzheimer?
- Anticholinesterases
- once per day
- increases level of ACH in synapse –> treats AD
- Reversible cholinesterase inhibitor.
- Long plasma half-life
How do Rivastigmine act as treatment for Alzheimer?
- Anticholinesterases
- Pseudo-reversible AChE & BChE inhibitor
- 8 hour half-life
- Reformulated as transdermal patch
How do galantamine act as treatment for Alzheimer?
- Anticholinesterases
- Reversible cholinesterase inhibitor
- 7-8 hour half-life
- alpha7 nAChR agonist
- only available orally
- partial agonist of neuronal nicotinic ach receptors
How do Memantine act as treatment for Alzheimer?
- NMDA receptor blocker
- Use-dependent non-competitive NMDA
- receptor blocker with low channel affinity
- Only licensed for moderate-severe AD
- Long plasma half-life
Gamma secretase inhibitor failed as a treatment drug –> but what was its mechanism of action?
Tarenflurbil & Semagacestat
- -> Tarenflurbil binds to amyloid precursor protein (APP) molecule
- -> Semagacestat is a small molecule gamma-secretase inhibitor
B-amyloid immunotherapy failed as a treatment drug –> but what was its mechanism of action?
Bapineuzumab & Solanezumab
- -> Humanised monoclonal antibodies
- -> targets diff variants of b-amyloids
Aducanumab?
Vaccines also in early stages of development
Tau inhibitors = failed as a treatment drug –> but what was its mechanism of action?
Tau inhibitors
Methylene blue
–> Licensed for the treatment of methaemoglobinaemia (and perhaps AD)
