Neurobiology of AD.

Question 1

What are the deleterious effects of AB oligomers?

Answer 1

Recent evidence suggests that it may not primarily be the plaques that are causing damage, as these form at a relatively late stage. Oligomers have been shown to be produced by a neuron-astroglial co-operativity. The oligomers themselves are- synaptotoxic: they cause damage of synpases - causing mitochondria damage - oxidative stress - tau hyperphosphorylation

Question 2

What are the effects of AB oligomers on oligodendrocytes?

Answer 2

Oligodendrocytes are particularly sensitive to the oxidative stress caused by AB oligomers. This is because they have:

• low level of reduced glutathione
• increased levels of iron.
  This reduces their abilitity to scavenge reactive oxygen species.

AB is particularly damaging to cholesterol rich membranes such as those found in ODG

Question 3

How does production of AB oligomers result in a positive feedback?

Answer 3

Eventually they form plaques, resulting in microglial activation. Microglia release IL-1b and TNF-a.

This stimulates the astrocyte–neuron to produce further amounts of Ab42 oligomers.

AB oligomers also activate RAGE receptor, resulting in upregulation of BACE-1 and further production of AB.

Question 4

What is the neurotoxic cascade of events between neurons and astrocytes in AD?

Answer 4

1. A threshold of AB42 production is reached and AB42 oligomers spill out of neurons.
2. They bind the a-7nAChRs (amongst many other receptors including calcium sensing receptor and NMDA) of its partner astrocytes causing astrocytes to exocytose the glutamate they have been taking up from the neuronal synapses.
3. Activation of neural NMDARs result in Ca2+ surges: dysfunctional mitochondria pumping out ROS, which inflict an oxidative damage, tau hyperphosphorylation.
4. Destruction of dendritic spines and neuronal synapses and severing communications within the astrocyte’s neurons and beyond.
5. Blocking calcium sensing receptor (activated by AB42 oligomers on neurons and astrocytes) blocks this chain of events

Question 5

Which therapies are currently licensed for AD?

Answer 5

• acetylcholinesterase inhibitors (rivastigmine)
• nAChR agonists (galantamine)
• NMDAR antagonists (memantine)

Question 6

What therapies are currently in development for AD?

Answer 6

• B secretase inhibitors
• Amyloid-beta active immunisation therapy
• amyloid/tau vaccination

Question 7

What is the name for amyloid build up in the cerebral vessels?

Answer 7

Cerebral Amyloid Angiopathy (CAA)

Question 8

Beside the main ones in clinical trials, what are some other potential therapeutic avenues in AD?

Answer 8

• PKC activatiors (PKC stimulates a-secretase, which carries out non-amyloidogenic pre-processing of APP)
• Somatostatin (Activates neprisylin which clears amyloid
• GSK-3 inhibitors (phosphorylates tau - hyperphosphorylated tau destabilises and tangles). Lithium and valproate both inhibit GSK-3

Question 9

What are the bodies natural clearance mechanisms for AB

Answer 9

1. proteolytic degradation by the proteases neprilysin and insulin degrading enzyme (IDE)
2. uptake by astrocytes and microglia
3. passive flow into the cerebrospinal fluid
4. sequestration into the vascular compartment by soluble form of the low-density lipoprotein receptor related protein 1 (LRP1)

Question 10

What are the four main hypothesis of AD?

Answer 10

1. Amyloid - brain degerenation caused by abberent APP processing and consequence AB toxic plaque formation and AB oligmer toxicity
2. Acetylecholine - Large decrement in ACh in the AD brain, ACh neurons in hippocampus are the first to be affected.
3. Inflammation - Signs of inflammation and immune response in AD brain
4. Tau - Tau becomes hyperphosphorylated, causing breakdown of microtubules, disruption of neural transport, tau tangles and cell death