Summary: The heat generated by amyloid beta aggregation can cause other, healthy amyloid beta to aggregate, causing more and more aggregates to form. However, by adding a novel active ingredient, the amyloid beta aggregation can be stopped and the cell temperature lowered.
Source: University of Cambridge
Researchers have shown that aggregation of amyloid-beta, one of two key proteins implicated in Alzheimer’s disease, causes cells to overheat and “fry like eggs”.
The University of Cambridge researchers used sensors small and sensitive enough to detect temperature changes in individual cells and found that when amyloid-beta misfolds and clumps together, it causes cells to overheat.
In an experiment using human cell lines, the researchers found that the heat released by the aggregation of amyloid beta could potentially cause other, healthy amyloid beta to aggregate, causing more and more aggregates to form.
In the same series of experiments, the researchers also showed that amyloid beta aggregation can be stopped and the cell temperature lowered by adding an active substance. The experiments also suggest that the compound has potential as a therapeutic for Alzheimer’s disease, although extensive testing and clinical trials would be required first.
The researchers say their assay could be used as a diagnostic tool for Alzheimer’s disease or to screen for potential drug candidates.
The results are reported in the Journal of the American Chemical Society.
Alzheimer’s disease affects an estimated 44 million people worldwide and there is currently no effective diagnosis or treatment. In Alzheimer’s disease, amyloid-beta and another protein called tau build up into tangles and plaques — collectively known as aggregates — causing brain cell death and brain shrinkage. This leads to memory loss, personality changes, and difficulty performing daily tasks.
It is a difficult disease to study because it develops over decades and a definitive diagnosis can only be made after examining samples of brain tissue after death. Which biochemical changes in a cell lead to the aggregation of amyloid-beta is not yet known.
In the research group of Prof. Gabriele Kaminski Schierle at the Department of Chemical Engineering and Biotechnology in Cambridge, they investigated the possible connection between temperature and amyloid beta aggregation in human cells.
The field of studying temperature changes within a cell is known as intracellular thermogenesis. It’s a new and challenging field: Scientists have developed sensors that can measure temperature changes, but nobody has ever tried to use these sensors to study conditions like Alzheimer’s disease.
“Thermogenesis has been linked to cellular stress, which could promote further aggregation,” said Chyi Wei Chung, the study’s first author. “We believe that when there is an imbalance in the cells, for example when the amyloid beta concentration is a little too high and accumulates, the cell temperature rises.”
“Overheating a cell is like frying an egg — when it gets hot, the proteins clump together and become dysfunctional,” said Kaminski Schierle, who led the research.
Researchers used tiny temperature sensors called fluorescent polymer thermometers (FTPs) to study the link between aggregation and temperature. They added amyloid-beta to human cell lines to boost the aggregation process and used a chemical called FCCP as a control, as it is known to trigger a rise in temperature.
They found that when amyloid-beta began to form thread-like aggregates called fibrils, the average temperature of the cells began to rise. The increase in cell temperature was significant compared to cells to which no amyloid beta was added.
“When the fibrils expand, they release energy in the form of heat,” says Kaminski Schierle. “Amyloid beta aggregation requires quite a bit of energy to get going, but once the aggregation process begins, it speeds up and releases more heat, allowing more aggregates to form.”
“Once the aggregates are formed, they can leave the cell and be taken up by neighboring cells, thereby infecting healthy amyloid beta in those cells,” Chung said. “Nobody has shown this relationship between temperature and aggregation in living cells before.”
Using a drug that inhibits amyloid beta aggregation, the researchers were able to identify the fibrils as the cause of thermogenesis. It was not known until now whether protein aggregation or possible damage to the mitochondria – the “batteries” that power the cells – are responsible for this phenomenon.
The researchers also found that the rise in cell temperature could be mitigated by treatment with an aggregation inhibitor, highlighting its potential as a therapeutic for Alzheimer’s disease.
The laboratory experiments were complemented by computer models that describe what might happen to amyloid-beta in an intracellular environment and why it might lead to an increase in intracellular temperatures. The researchers hope their work will stimulate new studies involving various parameters of physiological relevance.
Financing: The research 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).
About this news from Alzheimer’s research
Source: University of Cambridge
Contact: Sarah Collins – University of Cambridge
Picture: The picture is attributed to Chyi Wei Chung
Original research: Open access.
“Intracellular Aβ42 Aggregation Leads to Cellular Thermogenesis” by Chyi Wei Chung et al. Journal of the American Chemical Association
Intracellular Aβ42 aggregation leads to cellular thermogenesis
Aggregation of Aβ42 is a hallmark of Alzheimer’s disease. It is still unknown what biochemical changes take place within a cell that will eventually lead to Aβ42 aggregation.
Thermogenesis has been linked to cellular stress, the latter of which may promote aggregation.
We perform intracellular thermometric measurements using fluorescent polymer thermometers to show that Aβ42 aggregation leads to an increase in mean cell temperature in living cells. This temperature increase is moderated by treatment with an aggregation inhibitor of Aβ42 and is independent of mitochondrial damage that may otherwise result in thermogenesis.
With this, we present a diagnostic assay that could be used to screen for small molecule inhibitors against amyloid proteins in physiologically relevant settings. To interpret our experimental observations and motivate the development of future models, we perform classical molecular dynamics of model Aβ peptides to investigate the factors that hinder heat dissipation.
We observe that this is controlled by the presence of ions around it, the morphology of the amyloid peptides, and the extent of its hydrogen-bonding interactions with water.
We show that aggregation and heat storage are favored by Aβ peptides under intracellular-mimicking ionic conditions, which could potentially promote thermogenesis. The latter, in turn, will trigger further nucleation events that accelerate disease progression.