Mammalian cell stained with fluorescence polymeric thermometers and falsely-coloured based on temperature gradients. Credit: Chyi Wei Chung
Researchers have found that when amyloid-beta, which is one of two key proteins linked to Alzheimer’s disease, clumps together, it causes cells to get too hot and “fry like eggs.”
Researchers from the University of Cambridge used tiny sensors that were sensitive enough to pick up changes in temperature inside individual cells. They found that when amyloid-beta misfolds and forms clumps, it causes cells to get too hot.
In an experiment with human cell lines, researchers found that when amyloid-beta clumps together, they release heat that could cause other, healthy amyloid-beta to clump together, leading to more and more clumps.
In the same set of tests, the researchers also showed that a drug compound can stop amyloid-beta from clumping together and bring down the temperature of the cell. The tests also suggest that the compound could be used to treat Alzheimer’s disease, but more tests and clinical trials would need to be done first.
The researchers say that their assay could be used to find out if someone has Alzheimer’s disease or to test possible drugs. In the Journal of the American Chemical Society, the results are written up.
Alzheimer’s disease affects about 44 million people around the world, and there are no good tests or treatments for it right now. Amyloid-beta and another protein called tau build up into tangles and plaques in Alzheimer’s disease. This is called an aggregate, and it kills brain cells and makes the brain smaller. This leads to memory loss, changes in personality, and trouble with daily tasks.
It is hard to study this disease because it happens over a long period of time, and the only way to know for sure what is wrong is to look at samples of brain tissue after the person has died. No one knows yet what kinds of biochemical changes happen inside a cell that cause amyloid-beta to stick together.
Professor Gabriele Kaminski Schierle’s research group at Cambridge’s Department of Chemical Engineering and Biotechnology has been looking into whether temperature affects how amyloid-beta clumps together in human cells.
Intracellular thermogenesis is the field of study that looks at how the temperature inside a cell changes. Scientists have made sensors that can measure changes in temperature, but no one has ever tried to use these sensors to study diseases like Alzheimer’s. It is a new and difficult field.
The first author of the study, Chyi Wei Chung, said that thermogenesis has been linked to cellular stress, which may lead to more clumping. “We think that cellular temperatures rise when there is an imbalance in cells, like when the amount of amyloid-beta is slightly too high and it starts to build up.”
“Overheating a cell is like frying an egg—as it gets hotter, the proteins start to clump together and stop working,” said Kaminski Schierle, who led the research.
Researchers used fluorescent polymeric thermometers (FTPs), which are tiny temperature sensors, to study the link between aggregation and temperature. They added amyloid-beta to human cell lines to start the process of clumping together. As a control, they used a chemical called FCCP, which is known to cause a rise in temperature.
They found that when amyloid-beta started to form thread-like groups called fibrils, the average temperature of the cells started to rise. When compared to cells that didn’t have any amyloid-beta added, the rise in temperature was big.
Kaminski Schierle said, “As the fibrils start to get longer, they give off energy in the form of heat.” “Amyloid-beta aggregation takes a lot of energy to get started, but once it’s going, it speeds up and gives off more heat, which lets more aggregates form.”
“Once the aggregates have formed, they can leave the cell and be taken up by neighbouring cells, infecting healthy amyloid-beta in those cells,” said Chung. “This link between temperature and the way live cells stick together has never been shown before.”
Researchers were able to find that the fibrils were the cause of thermogenesis by using a drug that stops amyloid-beta from sticking together. Before, no one knew if this was caused by protein clumping or by possible damage to mitochondria, the “batteries” that give cells their energy.
The researchers also found that an aggregation inhibitor could stop the temperatures of cells from rising, showing that it could be used as a treatment for Alzheimer’s disease.
In addition to the lab experiments, computer models were used to show what might happen to amyloid-beta inside a cell and why that might cause the temperature inside the cell to rise. The researchers hope that their work will lead to new studies that look at different physiologically relevant parameters.
Further information: Chyi Wei Chung et al, Intracellular Aβ42 Aggregation Leads to Cellular Thermogenesis, Journal of the American Chemical Society (2022). DOI: 10.1021/jacs.2c03599
Journal information: Journal of the American Chemical Society
Source: University of Cambridge