Alzheimer's disease

Question 1

Main risk factor for Alzheier’s

Answer 1

Age (65+)

Question 2

`Leading causes of death in the UK

Answer 2

research investment

Nov 2016 – ONS announces AD & d

Question 3

Clnical symptoms of AD

Answer 3

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

Question 4

What is the genetics assocated with AD

Answer 4

APP, PSEN, (both increase early onset alzeimers)

ApoE (hereditary ~ 8%) … more prevalent, increases likelihood of late stage alzheimers disease

Question 5

Outline the amyloid hypothesis - physiological hypothesis

Answer 5

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

Question 6

What is the amyloid hypothesis- Pathophysiological processing

just clarify here this happens

Answer 6

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)

Question 7

Outline the Tau hypothesis - physiology

Answer 7

Soluble protein present in axons

Important for assembly & stability of microtubules

Question 8

Outline tau protein pathophysiology

Answer 8

Hyperphosphorylated tau is insoluble leads to self-aggregates to form neurofibrillary tangles

These are neurotoxic
This also results in microtubule instability

INTRACELLULAR

Question 9

What happens to the Ab proteins produced in amyloid hypothesis

Answer 9

They are monomers that can dimerise, trimerirse etc.

this forms plaques which likely leads to cell death

Question 10

Physiology of inflammation hypothesis- physiology

Answer 10

Specialised CNS immune cells - similar to macrophages

Question 11

Pathophysiology of inflammation hypothesis

Answer 11

Pathophysiology - Microglia

Increased release of inflammatory mediators & cytotoxic proteins

Increased phagocytosis

Reduced levels of neuroprotective proteins

Question 12

What would you expect of someone taking ibuprufen in terms of likelihood to develo alzheimers

Answer 12

Less likely maybe because of less inflammation

Question 13

Drug types for amzheimers

Answer 13

Anticholinesterases

NMDA receptor blocker

Question 14

List the anticholinesterases

Answer 14

1. Donepezil
2. Rivastigmine
3. Galantamine

Question 15

What is the mechanism of donepezil action

Answer 15

Anticholinesterase

Reversible cholinesterase inhibitor.
Long plasma half-life

Stark symptom improvement but only for a year

Question 16

What is the mechanism of rivastigmine

Answer 16

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

Question 17

Outline the mechanism of actin of galantamine

Answer 17

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

Question 18

List a NMDA receptor blocker

Answer 18

Memantine

Question 19

What is the mechanism of action of memantamine

Answer 19

Use-dependent non-competitive NMDA receptor blocker with low channel affinity

Moderate-severe AD

Long plasma half life

Question 20

Why is NMDA receptor blocker usefull in AD

Answer 20

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)

Question 21

last slide won’t appear in exam

Answer 21

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