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University of Cambridge researchers find protein that misfolds in Alzheimer’s causes cells ‘to fry like eggs’



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University of Cambridge researchers have shown that cells overheat and “fry like eggs” due to the aggregation of amyloid-beta - one of the two main proteins implicated in Alzheimer’s disease.

They used tiny, sensitive sensors to detect changes inside individual cells in an experiment using human cell lines.

Mammalian cell stained with fluorescence polymeric thermometers and falsely-coloured based on temperature. Image: Chyi Wei Chung (57234737)
Mammalian cell stained with fluorescence polymeric thermometers and falsely-coloured based on temperature. Image: Chyi Wei Chung (57234737)

Amyloid-beta normally plays an essential role in neural growth and repair. But the new research shows when it misfolds and clumps together, as is seen in Alzheimer’s and other neurodegenerative diseases, it causes cells to overheat - and the heat released could potentially cause other, healthy amyloid-beta to aggregate, causing more aggregates to form.

But the researchers also showed the aggregation can be stopped and the cell temperature lowered with the addition of a drug compound.

Extensive tests and clinical trials would be required to show if it has the potential to treat Alzheimer’s.

But the researchers in Prof Gabriele Kaminski Schierle’s research group at the Department of Chemical Engineering and Biotechnology say the assay could be used as a diagnostic tool for Alzheimer’s or to screen potential drug candidates.

Prof Kaminski Schierle, who led the research, said: “Overheating a cell is like frying an egg – as it heats up, the proteins start to clump together and become non-functional.”

Intracellular thermogenesis - the challenging new field of studying temperature changes inside a cell - has never before been tried to study conditions such as Alzheimer’s.

“Thermogenesis has been associated with cellular stress, which may promote further aggregation,” said Chyi Wei Chung, the study’s first author. “We believe that when there’s an imbalance in cells, like when the amyloid-beta concentration is slightly too high and it starts to accumulate, cellular temperatures increase.”

The tiny sensors used are called fluorescent polymeric thermometers (FTPs).

Amyloid-beta was added to human cell lines to start the aggregation process, with a chemical called FCCP used as a control since it is known to induce an increase in temperature.

As amyloid-beta started to form thread-like aggregates called fibrils, the temperature of the cells rose.

“As the fibrils start elongating, they release energy in the form of heat,” said Prof Kaminski Schierle. “Amyloid-beta aggregation requires quite a lot of energy to get going, but once the aggregation process starts, it speeds up and releases more heat, allowing more aggregates to form.”

“Once the aggregates have formed, they can exit the cell and be taken up by neighbouring cells, infecting healthy amyloid-beta in those cells,” added Chung. “No one has shown this link between temperature and aggregation in live cells before.”

The researchers used a drug that inhibits amyloid-beta aggregation to pinpoint the fibrils as the cause of thermogenesis. Previously, it was not known whether protein aggregation or potential damage to mitochondria – the ‘batteries’ that power cells – was responsible.

Computational modelling was also used to describe what might happen to amyloid-beta in an intracellular environment.

The researchers hope their work will provoke new studies incorporating different parameters of physiological relevance.

The research, published in the Journal of the American Chemical Society, was supported in part by Alzheimer’s Research UK, the Cambridge Trust, Wellcome, and the Medical Research Council, part of UK Research and Innovation (UKRI).



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