Clinical Update - Alzheimer's: It is thought that in Alzheimer’s disease, accumulations of amyloid deposits (amyloid-beta, known as Ab) destroy synapses, the major communication networks in the brain.

Work by a group led by Dr Cora O’Neill, Senior Lecturer in Biochemistry at UCC, has focused on trying to find affected pathways in the brains of people who have had Alzheimer’s disease. The aim is to explore the causes of neuro-degeneration.

In relation to Alzheimer’s, Dr O’Neill’s team has recently focused on insulin and insulin-like growth factor (IGF) signalling in the brain. This activates a kinase pathway called Akt, which is highly important in the activity of neurons. The UCC group has found many defects in that pathway in subjects with Alzheimer’s disease. Work is continuing to determine whether this is due to amyloid build-up or other factors.

A lot of energy has been spent targeting the Ab itself – as a possible new treatment strategy for Alzheimer’s disease. “To date, this has not unfortunately been as successful as people would like. It is not really understood why,” Dr O’Neill explained.

Some believe this is because interventions do not begin early enough. Amyloid damage is being targeted when the person may already have had the disease (and also defects in Ab biology and function) for many years. Current thinking proposes that Ab may have to be targeted at a very early stage, when it is in a small, soluble oligomeric form and before extensive damage is done (before symptoms even emerge).

In addition, it may be important therapeutically to target the pathways that these Ab oligomers affect in the brain at early stages of Alzheimer’s disease – including insulin and insulin-like growth factor signaling. In line with this, recent research by Prof Sandra Rossie of Purdue University has shown that increasing the amount of the protein phosphatase 5 (PP5) prevents neuronal death by amyloid beta and shuts off stress pathways.

Neurons with reduced PP5 are more sensitive to death caused by Ab. It was shown that PP5 was decreased in Alzheimer’s disease. The researchers worked forward to show that if you do not have PP5, there can be damage due to amyloid build-up.
Amyloids present a stress and ‘if stress pathways remain active for a prolonged period, the cell will die’, said Prof Rossie, whose research is at an early stage.

Dr O’Neill works on similar pathways – of which there are many – in the brain.

Pinpointing the key systems affected in the brain at the earliest stages of Alzheimer’s offers the promise of better treatments and earlier diagnosis