Step forward in linking metals to Alzheimer’s disease

Researchers from the Parkville-based Mental Health Research Institute believe that the toxicity of amyloid plaques found in the brains of people with Alzheimer’s is related to trapping essential zinc, which is needed for communication between brain cells.

First author Dr Paul Adlard said: “What appears to be happening in Alzheimer’s disease is that not only is there a drop in the level of ZnT3 but amyloid is also soaking up the zinc.”

“Amyloid is a big zinc fly trap”, said group Leader Professor Ashley Bush.

The study, published recently in Journal of Neuroscience, investigated the role of zinc and its transport protein ZnT3 in mice aged three months and six months.

By putting mice through the Morris water maze, which gauges spatial learning and memory, researchers found that there were obvious losses in learning and memory in the older mice accompanied by neurological and cognitive changes similar to Alzheimer’s disease. This was not the case in the younger mice.

“The list of what can go wrong is impressive,” said Dr Adlard.

The research showed that at any age mice without ZnT3 had about one third less brain zinc than mice with the transport protein. However even those mice had a 12 per cent drop in brain zinc levels between three and six months, indicating some zinc loss occurs with age.

“We found that the decrease in the zinc transporter (ZnT3) occurred in both mice and people (48 – 91 years), which was a surprise given that ZnT3 regulates brain zinc levels and hence might be expected to rise to counteract age-associated cognitive slow-down,” added Professor Bush.

These findings end more than 10 years’ of controversy about the role of zinc and its transport protein that was fuelled by a 1999 study which, despite expectation, did not show any signs of cognitive decline in mice at six to ten weeks old. “This seemed at odds with what was known about zinc and its role in brain health, learning and memory,” said research leader Dr Paul Adlard.

Dr Paul Adlard, said, “However, we now recognise that the original research did not look for cognitive impairments in old enough mice”.

The implications of this recent Melbourne finding are of great importance given the huge numbers of people affected by age-related cognitive loss and Alzheimer’s disease.

Of particular importance is the impact of amyloid upon the zinc system within the brain, and drugs being developed that target that abnormality.

“This mechanism could relate to the action of the zinc/copper regulating drug PBT2, which boosts cognition in mice with Alzheimer’s disease,” said Professor Bush.

The compound has shown promise in the clinic, improving certain cognitive measures in a Phase 2a trial of patients with mild Alzheimer’s disease. The drug appears to be taking the zinc out of amyloid and returns it to the cell. Further clinical trials are expected this year.

The Mental Health Research Institute researchers have now started work investigating potential therapies based on the results of this latest study into zinc and its effect on the brain.

“With these results, we are now able to target this loss of zinc and ZnT3 by using compounds that help shuttle metals into the cells that need them” said Dr Adlard.

The investigation was undertaken by Paul Adlard, Jacqui Parncutt, David Finkelstein and Ashley Bush. The Mental Health Research Institute is a leader in research that improves the lives of people affected by mental illnesses and dementia. It undertakes sustainable, high quality, basic scientific, clinical and public health research.

The Institute’s Alzheimer’s disease research group led by Professor Colin Masters and Professor Ashley Bush is internationally recognised as a world leader in Alzheimer’s disease research.