Alzheimer’s Disease First Steps Revealed by Mouse Brain in a Dish

Using slices of mouse brain tissue kept alive in a lab dish, scientists have identified the earliest molecular changes leading to Alzheimer’s disease.

The findings, showing how early alterations in brain amyloid-β balance causes nerve connections called synapses to die, might allow scientist to target the mechanisms and develop therapies to prevent or postpone disease.

Once a patient receives an Alzheimer’s diagnosis, extensive brain changes involving deposits of amyloid-β protein, referred to as plaque, are already present.

Identifying the first steps leading to Alzheimer’s is a crucial step towards the development of a drug capable of this task. Until now, science has been hampered by poor models of the disease, studying brains of deceased patients or mice bred to mimic human brain conditions.

The new method, developed by researchers at Babraham Institute is a big advance, allowing researchers to track changes as they occur in real-time. Because the tissue in the dish retains its three-dimensional structure and function, it is likely to react similarly to a living brain when exposed to drugs or other experimental conditions.

The study, “Synaptophysin depletion and intraneuronal Aβ in organotypic hippocampal slice cultures from huAPP transgenic mice,” published in the journal Molecular Neurodegeneration and supported by the non-profit organization Alzheimer’s Research U.K., used a brain region called the hippocampus, involved in memory and emotional processes.

The research team isolated brain tissue from young mice engineered to develop Alzheimer’s disease as they grew old. Keeping the tissue alive in a dish, researchers noted that amyloid-β began to build up in the brain slice as it grew older. The buildup of protein could be linked to a loss of proteins in synaptic connections, crucial for the transmission of nerve signals.

Treating the slices with a drug lowered the amount of amyloid-β and restored synaptic protein production. The findings show the value of such a model system for screening potential drug candidates.

“This technique will help us to observe the earliest, usually hidden, stages of Alzheimer’s disease (while) providing an accessible system for the identification of promising treatments,” said Claire Harwell, a Ph.D. student at the Babraham Institute and first author on the paper, in a press release. “For effective therapeutics to be developed, we must understand and target the disease at its earliest stages.”

Senior study author Michael Coleman, research group leader at the Babraham Institute and professor of Neuroscience at the John van Geest Centre for Brain Repair, said the system lets candidate drugs be readily delivered and the effect monitored closely.

“Thus (we are) filling a vital gap between cell culture and animal studies. We expect that this approach will be extremely useful in research into Alzheimer’s disease and potential treatments,” Coleman said.

Dr. Simon Ridley, Director of Research at Alzheimer’s Research U.K.,  said the development of new treatments for Alzheimer’s requires innovative research techniques that include using brain tissue in a lab dish – because the human brain is a very inaccessible organ.

“It’s important for scientists to use a range of approaches to understand different aspects of Alzheimer’s and this new research provides a window into some of the early stages of the disease process. Research such as this has the power to open new doors to studies in humans and to help in the search for new treatments for this devastating disease,” Ridley said.

According to a 2015 trajectory report by the Alzheimer’s Association, about 13.5 million people could have Alzheimer’s disease in 2050. If treatments were made available that could delay the disease by five years, only 7.9 million would be affected.