Alzheimers - Aetiology

Question 1

Main Pathological Hallmarks of AD

Answer 1

Neurofibrillary Tangles (hyperphosphorylated tau) and Amyloid Beta derived senile plaques

Question 2

What is Amyloid Beta?

Answer 2

Peptide of 38-43 residues (pathogenic variant is 42 residues). Proteolytic product from sequential cleavage of larger APP

Question 3

What is the Function of APP?

Answer 3

Includes nervous system development, formation and function of neuromuscular junction, synaptogenesis and synaptic functions including synaptic plasticity

Question 4

What is the most common cause of Familial AD?

Answer 4

Mutations in PS1 altering activity of cleavage of APP at gamma cleavage site. Mutations in PS2 and APP genes also can cause FAD

Question 5

Name the type of protein which does NOT cause production of Amyloid beta?

Answer 5

Alpha secretase (ADAM10, ADAM17(TASE)) that are activated by furin-type convertase

Question 6

What are the beta secretases called and where are they located?

Answer 6

BACE1/2 - Beta APP cleavage Enzyme. Located predominantly in golgi/endosomes

Question 7

How does AB cause Alzheimers?

Answer 7

Causes neuronal loss before plaques form. AB must be neurotoxic and is found to affect homeostasis of glutaminergic system and increase depression of long term potentiation

Question 8

Natural function of AB

Answer 8

Found in CSF- leads to a decrease in synaptic activity
Production of AB increased by neuronal activity to inhibit fast excitatory synaptic transmission

Question 9

What form of AB causes neurotoxicity

Answer 9

Oligomeric AB is the main suspect behind neurotoxicity in AD

Question 10

Suggested Synaptotoxic pathway of AB

Answer 10

AB binding to alpha7-nicotinic receptor induces cascade that leads to endocytosis of NMDA receptor and depression of NMDA mediated currents

Question 11

Relationship between AB and the presynapse

Answer 11

Low levels of AB reduce presynaptic efficacy, and intermediate levels lead to presynaptic facilitation leading to synaptic potentiation

Question 12

Why is memantine used to treat AD?

Answer 12

It is an NMDA blocker. In AD excessive stimulation of glutamate receptors is thought to occur at early stages which would lead to excitotoxicity

Question 13

Describe the amyloid cascade hypothesis

Answer 13

Accumulation of Ab42 in limbic system
- Ab oligmers affect synaptic efficacy
- deposition as plaques in the brain
- microglial and astrocyte activation/inflammatory response
- Altered neuronal ionic homeostasis, oxidative injury
- altered kinase/phosphotase activity from Ab oligomers leading to Nf tangles
- Widespread neuronal/synaptic dysfunction with selective neuronal loss

Question 14

what regions of the brain are primarily affect by AD?

Answer 14

Entorhinal cortex and hippocampus and primarily affected

Question 15

How is the transmission of amyloid beta pathology described?

Answer 15

Prion-like transmission

Question 16

What were the results of AB vaccination trials

Answer 16

Showed little to no protection from dementia - could be due to immunizations starting too late

Question 17

What are therapies for AD

Answer 17

Anti-inflammatories
Neuronal activity inhibitors
Ab vaccination (immunotherapy)
Targets for Secretases (agonists of a-secretase,
inhibitors of b and y secretase)

Question 18

What is the problem with BACE1 inhibitors and what new studies could help pharmocodynamically?

Answer 18

BACE1 is a major drug target that successfully lowers AB in brain and CSF. Many studies terminated early due to side effects/non-progressive cognitive worsening.
BACE1 has now been shown to modulate gp130 function, soluable gp130 mmay serve as a pharmacodynamic activity marker to reduce side effects of chronic BACE1 inhibition.

Question 19

Where do Tau tangles originate?

Answer 19

Start in somatodendritic compartment of neurones in the entorhinal cortex and then to hippocampus

Question 20

What neurones are most affected by AD?

Answer 20

Cholinergic neurones in the basal forebrain

Question 21

How do tau tangles affect neurones?

Answer 21

Tau aggregates in neurone body, blocking neurone transport systems and potentially displacing organelles

Question 22

Can misfolded tau pass between neurones?

Answer 22

Yes, in a prion-like manner