25. Alzheimer's disease Flashcards Preview

pharm > 25. Alzheimer's disease > Flashcards

Flashcards in 25. Alzheimer's disease Deck (18)
Loading flashcards...
1
Q

what is the main risk factor for Alzheimer’s disease?

A

age

2
Q

what are the genetic components to Alzheimer’s?

A
  1. mutations in the amyloid precursor protein (APP) –> early onset
  2. mutations in presenilin gene (PSEN) –> increased likelihood of early onset
  3. Apo Lipoprotein E (ApoE) mutation –> increased likelihood of late onset
3
Q

what are the clinical symptoms of Alzheimer’s disease?

A
  • memory loss (especially recently acquired information)
  • disorientation/confusion
  • language problems
  • personality changes
  • poor judgement
4
Q

what is the beta amyloid hypothesis of Alzheimer’s?

A

there is an accumulation of beta amyloid plaques within the brain/CNS

5
Q

how should APP be processed?

A
  1. APP is cleaved by a-secretase
  2. sAPP-alpha is released but the C83 fragment remains
  3. C83 is digested by gamma-secretase and the products are removed
6
Q

how does the beta-amyloid hypothesis suggest APP is processed in Alzheimer patients?

A
  1. APP in cleaved by b-secretase
  2. sAPP-beta is released but the C99 fragment remains
  3. C99 is digested by gamma-secretase, releasing b-amyloid protein
    - b-amyloid protein forms toxic aggregates –> formation of beta-amyloid plaques
7
Q

what is Tau protein and why is it important?

A

a soluble protein present in neuronal axons - forms the internal skeleton of neuronal cells

it is important for the assembly and stability of microtubules

8
Q

what is the Tau hypothesis of Alzheimer’s?

A

hyper-phosphorylated Tau is insoluble –> self aggregates to form neurofibrillary tangles

these are neurotoxic –> results in microtubule instability

9
Q

what are microglia?

A

specialised CNS immune cells - similar to macrophages

10
Q

what is the inflammation hypothesis?

A
  • inappropriate activation of microglial cells
  • increased release of inflammatory mediators and cytotoxic proteins
  • increased phagocytosis
  • decreased levels of neuro-protective proteins
11
Q

what 2 categories of drugs do Alzheimer drugs fall into?

A
  • anticholinesterases

- NMDA receptor blocker

12
Q

list the 3 anticholinesterase drugs and outline their key features

A
  1. donepezil
    - reversible cholinesterase inhibitor
    - long plasma life
  2. pseudo-reversible AChE/BChE (butyrylcholinesterase) inhibitor
    - short half life
    - reformulated as transdermal patch formulation
  3. Galantamine
    - reversible cholinesterase inhibitor
    - short half life
13
Q

what does inhibition of butyrylcholinesterase enzyme lead to?

A

side effects such as liver problems

14
Q

what is the NMDA receptor blocker used to treat Alzheimer’s disease and what are its key features?

A

Memantine

  • only licensed for moderate/severe Alzheimer’s
  • use-dependent non-competitive NMDA receptor blocker with low channel affinity
  • the more the NMDAr is activated, the more likely memantine is to have an inhibitory effect
  • long plasma half-life
15
Q

list 3 treatment failures for Alzheimer’s

A
  1. gamma-secretase inhibitors
  2. monoclonal antibodies for b-amyloid proteins
  3. Tau inhibitors
16
Q

name the gamma-secretase inhibitors and outline why they failed

A

Tarenflurbil and Semagacestat

  • Tarenflurbil (NSAID) binds to the APP molecule
  • Semagacestat increases morbidity because it causes skin cancer (inhibits the NOTCH pathway)
17
Q

name the monoclonal antibodies for b-amyloid proteins and outline why they failed

A

Bapineuzumab and Solanezumab

  • Bapineuzumab targets the oligomers of b-amyloid
  • Solanezumab has been shown to have some effect but is still generally ineffective
18
Q

name the tau inhibitor and outline why it has failed

A

methylene blue

  • licensed for the treatment of methaemoglobinaemia
  • still in phase 3 clinical trials