L24 - Alzheimers Disease

Question 1

x% of all cases of dementia are caused by AD - it is also the most common cause of dementia among >65 year olds

Answer 1

60

Question 2

If you have Amyloid-Beta in your brain, does this mean you have AD?

Answer 2

Not necessarily

Question 3

Majority of neurons affected in AD is in which brain region?

Answer 3

PFC

Question 4

What 2 abnormal structures are seen in brains of people with AD?

Answer 4

1) Beta-amyloid plaques - dense deposits of protein and cellular material that accumulate around nerve cells, WE THINK it creates a toxic environment
2) Neurofibrillary tangles - twisted fibres that build up inside the nerve cell caused by hyperphosphorylation of tau protein

Question 5

What is the precursor to amyloid peptide (A-beta)?

Answer 5

APP - amyloid precursor protein, it has 3 cleavage sites alpha, beta and gamma

Question 6

What enzymes do you need to cleave APP to A-Beta (beta-amyloid protein)?

Answer 6

Beta-secretase AND Gamma-secretase

Question 7

If you have mutation in the A-Beta gene, you get greater cleavage where?

Answer 7

Beta-secretase so you produce more A-beta toxic fragment

Question 8

Which secretase combination: alpha, beta, gamma is neuroprotective?

Answer 8

alpha and gamma

Question 9

T/F - Hyperphosphorylation of tau is in same regions to the amyloid plaques in the brain

Answer 9

F- different

Question 10

T/F -Higher incidence of AD in people that drink, smoke, inactive, overweigh

Answer 10

T

Question 11

How are neurofibrillary tangles formed?

Answer 11

Tau protein stabilizes the cell usually, in AD, abnormal tau fall apart from microtubules - destroying the transport system. Strands of the abnormal tau then form neurofibrillary tangles

Question 12

How does the PET scan of AD-affected brain differ from normal brain? MRI?

Answer 12

PET - Decreased cellular activity (not using as much glucose)

MRI - atrophy present in AD brain

Question 13

Using specific ligands that can bind to amyloid - in AD brain, there is more amyloid present

Answer 13

Using specific ligands that can bind to amyloid - in AD brain, there is more amyloid present

Question 14

Preclinical AD - in which areas are the first signs of AD seen?

Answer 14

Entorhinal cortex -> then hippocampus (BOTH MEMORY-IMPORTANT REGIONS)

• Affected regions shrink as nerve cells die
• Changes can begin 10-20 years before symptoms appear

Question 15

You can take CSF and look at ____ which is the toxic component - these are also found in presymptomatic individuals

Answer 15

ABeta42

Question 16

AD is linked with deficiency of what NT?

Answer 16

Ach - basal forebrain inputs to hippocampus and cerebral cortex impaired

Question 17

Donepezil (Aricept is brand name)

a) What is it?
b) Features - comp/non-comp, reversible/irreversible, half life?
c) Dosage?
d) Metabolised by?
e) Delays AD by how long?
f) Adverse effects?

Answer 17

a) Anticholinesterase used to treat AD
b) Non-comp and irreversible in terms of binding and have similar efficacy, with half life of 70 hours
c) Once a day 5 to 10 mg
d) Metab by cytochrome P450 isoenzymes CYP3A and CYP2D6
e) Delays deterioration by 6- 12 months
f) SE: Nausea, diarrhoea, anorexia, headache, insomnia, depression, drowsiness, dizziness, fatigue, sweating, tremor, muscle cramps

Question 18

Does vitamin E have an effect in AD or CV disease?

Answer 18

No

Question 19

There is quite a few antidepressants and antipsychotics that are used to treat the symptoms of AD

Answer 19

There is quite a few antidepressants and antipsychotics that are used to treat the symptoms of AD

Question 20

In AD patients, there is a dramatic decrease in levels of _____ in the cortex and hippocampus due to the atrophy of _____ where the cholinergic inputs are primarily from

Answer 20

Choline acetyltransferase, nucleus basalis of Meynert in basal forebrain

Question 21

Cholinergic hypothesis

Answer 21

Loss of ACh in AD correlates with impairment of memory - hence enhancement of cholinergic function may improve cognitive function

Question 22

Another drug approved for AD?

Answer 22

Memantine - NMDA antagonist, reduce glutamate-induced neuronal degeneration

Question 23

Current treatment summary of AD

Answer 23

Cholinergic agents initially improve and transiently maintain cognitive abilities in patients with mild to moderate AD.

However, cognitive abilities worsen over time, treatment may delay but does not stop AD progression

New treatments that maintain cognitive ability and stop the progression of AD are needed

Question 24

If you have a higher incidence of APOE4, there is a higher incidence in AD but we are not sure how it works - could have to do with endogenous clearance mechanisms

Answer 24

If you have a higher incidence of APOE4, there is a higher incidence in AD but we are not sure how it works - could have to do with endogenous clearance mechanisms

Question 25

What is IVIG (Intravenous immunoglobulin)

Answer 25

Pooled IgG antibodies extracted from plasma and used to treat autoimmune diseases by reducing inflammation

Question 26

Part of the amyloid fragment is held together by transition metals - how does PBT2 target this?

Answer 26

PBT2 chelates these metals and the fragment can be dispersed and cleared

Question 27

Parabiosis of young to old animal shows that there is a factor in young blood (plasma) that reverses ageing phenotypes - can cause more neurogenesis in the hippocampus

Answer 27

Parabiosis of young to old animal shows that there is a factor in young blood (plasma) that reverses ageing phenotypes - can cause more neurogenesis in the hippocampus

Question 28

Amyloid Beta immunotherapy

We can use immunotherapy to have the bodies own immune system clear up A-Beta

Answer 28

Amyloid Beta immunotherapy

We can use immunotherapy to have the bodies own immune system clear up A-Beta

Question 29

Passive strategy - monoclonal antibody (bapineuzumab) that binds A-Beta fragments and then letting endogenous microglia clear it show that early anti-Abeta administration clears also non-phosphorylated tau

Answer 29

Passive strategy - monoclonal antibody (bapineuzumab) that binds A-Beta fragments and then letting endogenous microglia clear it show that early anti-Abeta administration clears also non-phosphorylated tau