Pharm 25 - Alzheimers Disease

Question 1

Whats the main risk factor for alzheimers

Answer 1

Age

Question 2

Name 2 genetic mutations that predispose to early onset AD

Answer 2

APP, PSEN

Question 3

Name a genetic mutation that predisposes to late onset AD

Answer 3

ApoE

Question 4

Name 5 symptoms associated with AD

Answer 4

1. Memory loss (esp recently acquired info)
2. Disorientation/confusion
3. Language problems
4. Personality changes
5. Poor judgement

Question 5

What are the 3 hypotheses as to the cause of AD

Answer 5

1. Amyloid hypothesis
2. Tau hypothesis
3. Inflammation hypothesis (less important than Amyloid/Tau hypotheses)

Question 6

Explain the amyloid hypothesis

Answer 6

On a neuronal cell, there are 3 species on the cell membrane - Gamma secretase, APP, alpha secretase

Physiologically - APP cleaved by a-secretase, which releases secreted APPa (sAPPa), leaving behind a C83 fragment. C83 fragment digested by gamma secretes - and products are removed.

Pathophysiologically - APP cleaved by b-secretase (not a-secretase), which release sAPPb, leaving behind a C99 fragment (instead of a C83 fragment). C99 is digested by gamma-secretase, which releases B-amyloid protein. B-amyloid protein forms toxic aggregates.

Pathophysiology caused by b-secretase instead of a-secretase

Question 7

Explain the tau hypothesis of AD

Answer 7

Tau protein = soluble protein present in axons that associates with microtubules

Physiology - tau proteins associate with microtubules and important for their assembly and stability

Pathophysiology - hyperphosphorylated tau = insoluble
Insoluble means that they self aggregate to form neurofibrillary tangles. These are neurotoxic and result in microtubule instability.

AD = hyperphosphorylation of tau proteins

(Tau hypothesis correlates better with the symptoms of AD than amyloid hypothesis but not solid)

Question 8

Explain the inflammation hypothesis for AD

Answer 8

Microglia = specilaised CNS immune cells - similar to macrophages

Physiology - microglia normal

Pathophysiology - Microglia have increased activity –> increased release of inflammatory mediators and cytotoxic proteins, increased phagocytosis, decreased levels of neuroprotective proteins

Question 9

What are the 2 general classes of drugs used to treat AD

Answer 9

1. Anticholinesterases

2. NMDA receptor blocker

Question 10

What are the 3 anti cholinesterase drugs used to treat AD

Answer 10

1. Donepezil - reversible cholinesterase inhibitor, long plasma half life
2. Rivastigmine - “pseudo-reversible” AChE and BChE inhibitor, 8 hour half life, can be given as a transdermal patch
3. Galantamine - reversible cholinesterase inhibitor, 7-8 hour half life, a7 NAChR agonist (partial agonist)

Question 11

What is galantamine a partial agonist of?

Answer 11

NEURONAL nAChR

Question 12

What is BChE and why is it important

Answer 12

Butyryl cholinesterase - it is found primarily in the liver (little bit in CNS) - you want to minimise BChE effects as it has more side effects.

This is why Rivastigmine is given transdermally

Question 13

What drug is a NMDA receptor blocker that is given. What is important about this drug

Answer 13

Memantine

It is a use-dependent non-competitive NMDA receptor - has low channel affinity

It has a long plasma half life

The more often the NMDAr is activated, the more effective Memantine is - XS NMDAr activation in neurodegeneration)

Question 14

Which drugs are used for early stage AD and which is used for late stage AD

Answer 14

Early stage AD:

1. Donepezil
2. Rivastigmine
3. Galantamine

These are anticholinesterases

Late stage AD:

1. Memantine (NMDA receptor blocker)

Question 15

Name a tau inhibitor that is used to treat methaemoglobinaemia

Answer 15

Methylene blue (NOT USED for AD)