Treating memory impairment

Question 1

Evidence in support of the synaptic dysfunction hypothesis of AD

Answer 1

• Pet imaging shows that synaptic dysfunction begins very early, in the preclinical stages of AD. This particular study showed it to be secondary to increased levels of amyloid beta (Jack, 2010), but it is hypothesised that synaptic dysfunction may begin even earlier.
• Complement cascades are involved in tagging synapses for degradation. It has been shown that complement cascades are upregulated in AD. These complement cascades are part of the neuroinflammation observed in AD, but it has been hypothesised that it is the synpatic loss that drives AD. (Stephan, 2012)
• Applying AB oligomers to neurons in vitro reduces LTP

Question 2

What are the currently licesened treatments for Alzheimers’s disease?

Answer 2

1. Anticholinesterase drugs - Preventing ACh breakdown thus increasing synaptic conc & longevity
2. Cholingergic agonists - galantamine (also weak AChE inhibitor - dual action)
3. NMDA receptor antagonists - memantine

Question 3

Why are rivastigmine and galantamine drugs used in AD?

Answer 3

Extensive loss of cholingergic innervation occurs even in early stages of AD. These drugs can therefore potentiate ACh activity in the remaining cholinergic neurons. They do not halt degeneration process, and are only effective for providing symptomatic relief for ≈ 1 year in early stages - until degeneration becomes too extensive.

Question 4

Why is memantine used for AD?

Answer 4

Is it a NMDA antagonist that prevents the prolonged influx of Ca++. This reduces excitotoxicity, and may therefore help to slow the process of cell death.

Question 5

What are iPSCs and what have they revealed about AD?

Answer 5

These are somatic cells taken from patients, which are then programmed into pluripotent stem cells uing Yamanaka factors. They can then be forced to differentiate into neurons, and the neuronal phenotype studied.

One experiment has taken 6 people - two with sporadic AD, two with familial and two non-demented controls and studied their iPSCs.

They found normal electrophsyiology of neurons. They reported increased AB production (in 3/4), increased p-tau (in 3/4) and increased GSK-3 activity (4/4). They found that inhibiting B-secretase but not gamma secretase reduced p-tau and GSK-3 activity, suggesting it is not AB oligomers activating tau pathways, but something in APP processing pathway.

Question 6

What are the limitations of iPSCs in AD research?

Answer 6

Highly expensive - only small n number means that results are only ever observations. It also means its impossible to know whether the result is due to the disease in study, or simply due to genetic variation of the individual.

Neurons are equivalent to fetal neurons, which are not that relevant to an age-related disease - although it is a very early timepoint for investigation so they could still provide some insight as to the eitological development of disease.

Question 7

How may Dickkopf-1 signalling be implicated in AD?

Answer 7

Dickkopf-1 is a downstream molecule of AB - it has been shown to have increased expression after AB application to neurons, and neurons exposed to either Dickkopf-1 or AB show the same reductions in spine density and spine area. Dickkopf-1 activates Wnt-PCP and tau pathology.

Wnt-PCP regulates actin cytoskeletal dynamics, via RhoA and ROCK. This may underlie synapse degeneration.
Fasuldil is a drug that blocks ROCK. It has been shown to ameliorate synaptic effects of AB and Dkk-1 administration to neurons in vitro, and to block the reduction in novel object recognition caused by AB administration.

Question 8

Solanezumab

Answer 8

This is a human monoclonal antibody that targets AB, sequestering it and targeting removal of small species.

It failed a phase 3 clinical trial, where it did not meet primary endpoints of slowing cognitive decline in mild AD patients. Primary endpoint was assessment of 11 types of cognitive impairment, secondary endpoint was assessment of ability to complete daily tasks. It approached therapeutic benefit for both measures but did not reach signficance.

It is currently in clinical trials as a prophylatic preventative treatment in preclinical asymptomatic amyloidosis patients, after recieving biomarker effects in phase 2 trials with asymptomatic patients containing familial AD genes.