Pharmacology: Alzheimer's Disease

Question 1

Name some proteins that when altered are associated with hereditary (early onset) cases of Alzheimer’s (8% of cases)

Answer 1

APP (amyloid precursor protein)
PSEN (presenilin protein- one of the four core proteins in the gamma secretase complex)
Apo E (Apolipoprotein E)

Question 2

Clinical Sx

Answer 2

Memory loss 
Disorientation/ confusion
language problems
Personality changes (fearful, anxious)
Poor judgement

Question 3

Explain the physiological processing of APP

Answer 3

1. APP cleaved by alpha-secretase
2. sAPPa released0 C83 fragment remains
3. C83 –> digested by gamma-secretase
4. protein produced

Question 4

Explain the pathophysiological processing of APP

Answer 4

1. APP cleaved by beta-secretase
2. sAPPb released- C(( fragment remains
3. C99 –> digested by gamma-secretase releasing bAP which forms toxic aggregates
   (these are within and primarily outside cell membranes

Question 5

What do Tau protein do within neurones?

Answer 5

Soluble protein present in axons.
Maintain integrity and assembly of the microtubules of neuronal axons (important for the transportation of material within the neurone)

Question 6

Describe the Tau hypothesis

Answer 6

Hyperphosphorylated tau is INSOLUBLE –> self-aggregated to form neurofibrillary tangles which are NEUROTOXIC.
This leads to microtubule instability.

Question 7

Describe the inflammation hypothesis

Answer 7

MICROGLIA (neuronal macrophages) involved.
Pathophysiology- increase release of inflam med and cytotoxic proteins.
Increased phagocytosis
Decreased levels in neuroprotective protein

Question 8

Name the current drug groups used to treat Alzhimer’s

Answer 8

1. Anticholinesterases

2. NMDA receptor blocker

Question 9

Name three anti-ACh drugs used and summarise their action

Answer 9

1. Donepezil*- reversible; long plasma t1/2
2. **Rivastigmine (pseudo-reversible ACh & BChE inhib; 8 hr t1/2; reformulated as transdermal patch- more selective to AChE so don’t get as many of the bad SEs of AChB
3. ** Galantamine- reversible; 7-8 hr t1/2; alpha 7 nAChR agonist

• Almost immediately reverses memory loss- max effect 2 year though. First line and sever forms
• • mild-moderate disease

Question 10

Name a NMDA receptor blocker and summarise its actions

Answer 10

Memantine
Use-dependent non-competitive receptor blocker with low channel affinity
Moderate and sever AD only
Long plasma t1/2

Question 11

Name three failed treatments

Answer 11

1. Gamma-secretase
2. beta-amyloid
3. Tau inhibitors

Question 12

Give some examples of gamma secretase inhibitors and describe their MOA

Answer 12

1. Tarenflurbil- binds APP molecule

2. Semagacestat- small molecule gamma-sec inhibitor- inhibits NOTCH enzyme- increasing skin cancer

Question 13

Give some examples of beta-amyloid and describe their MOA

Answer 13

1. Bapineuzamab- monoclonal ab

2. Aducanumab- targets b-amyloid monomer and fibrular aggregates

Question 14

Give some examples of tau inhibitors and describe their MOA

Answer 14

Methylene blue- already licenced for methaemoglobinaemia