Summary: The heat generated by amyloid-beta aggregation can lead to the formation of other, healthier amyloid-beta aggregates, leading to the formation of more and more aggregates. However, the addition of a new drug compound can stop the amyloid-beta aggregation and lower the cell temperature.
A source: University of Cambridge
Researchers have shown that the aggregation of amyloid-beta, one of the two major proteins involved in Alzheimer’s disease, can cause cells to overheat and “fry like eggs.”
Researchers at the University of Cambridge have observed that small and sensitive sensors detect changes in temperature inside individual cells, and that amyloid-beta bends and accumulates incorrectly, causing the cells to overheat.
In an experiment using human cell lines, the researchers found that the heat released from amyloid-beta aggregation could lead to the formation of another, healthy amyloid-beta aggregate, which in turn could lead to the formation of more and more aggregates.
In the same series of experiments, the researchers showed that a drug compound could be added by stopping amyloid-beta aggregation, lowering cell temperature. Experiments also show that the compound has the potential to treat Alzheimer’s disease, but extensive tests and clinical trials are required first.
According to the researchers, their analysis could be used as a diagnostic tool for Alzheimer’s disease or to screen potential drug candidates.
The results are reported Journal of the American Chemical Society.
Alzheimer’s disease affects approximately 44 million people worldwide and there are currently no effective diagnoses or treatments. In Alzheimer’s disease, another protein called amyloid-beta and mountain accumulates in the plaques and plaques, which are commonly referred to as aggregates — causing brain cells to die and the brain to shrink. As a result, memory is lost, personality changes, and it becomes difficult to perform daily functions.
This study is a difficult disease because it has developed over decades and the diagnosis can only be made after a thorough examination of brain tissue samples after death. It is still unknown what biochemical changes inside the cell lead to amyloid-beta aggregation.
Gabriele Kaminski, a professor at Cambridge’s Department of Chemical Engineering and Biotechnology, and Shearel’s research team are studying a possible link between temperature and amyloid-beta aggregation in human cells.
The field of study of changes in intracellular temperature is called intracellular thermogenesis. It’s a new and complex field: Scientists have developed sensors that measure changes in temperature, but no one has tried to use these sensors to study conditions such as Alzheimer’s disease.
“Thermogenesis has been linked to cellular stress, which may contribute to further aggregation,” said Chi Wei Chung, the study’s first author. “We believe that when there is an imbalance in the cells, for example, the amyloid-beta concentration is slightly higher, and when it begins to accumulate, the cell temperature rises.”
“The overheating of the cell is like frying an egg – when it heats up, the proteins combine and stop working,” said Kaminsky Schierle, who led the study.
Researchers used small temperature sensors called fluorescent polymer thermometers (FTPs) to study the relationship between aggregation and temperature. To start the aggregation process, they added amyloid beta to human cell lines and used a chemical called FCCP to control the temperature rise.
They found that they began to form filamentous aggregates called amyloid-beta fibrils, and that the average cell temperature began to rise. The increase in cellular temperature was significant compared to cells without amyloid-beta.
“When the fibrils start to lengthen, they release energy in the form of heat,” said Kaminski Schierle. “Amyloid-beta aggregation requires a lot of energy to get started, but when the accumulation process begins, it accelerates and releases more heat, allowing more aggregates to form.”
“Once the aggregates are formed, they leave the cell and are absorbed by neighboring cells, which can infect healthy amyloid-beta in those cells,” Chung said. “No one has shown such a relationship between temperature and aggregation in living cells before.”
Using a drug that stopped amyloid-beta aggregation, the researchers were able to identify fibrils as the cause of thermogenesis. It was previously unknown whether the protein aggregated or damaged the mitochondria, the “batteries” that power the cells.
The researchers also noted that the increase in cell temperature can be mitigated by treatment with aggregation inhibitors, and its potential to treat Alzheimer’s disease.
Laboratory experiments have been supplemented with computational modeling that describes what can happen to amyloid-beta in the intracellular environment and why it can lead to an increase in intracellular temperature. Researchers hope that their work will inspire new research by introducing various parameters of physiological relevance.
Funding: The study was partially supported by the Alzheimer’s Research in the UK, the Cambridge Trust, Wellcome and the Medical Research Council, which is part of the UK Research and Innovation (UKRI).
Research on Alzheimer’s disease
Author: Sarah Collins
A source: University of Cambridge
The connection: Sarah Collins – University of Cambridge
Photo: Photo by Chi Wei Chung
Original study: Open access.
“Intracellular Aβ42 aggregation leads to cellular thermogenesis” Chyi Wei Chung et al. Journal of the American Chemical Association
Intracellular Aβ42 aggregation leads to cellular thermogenesis
Aβ42 aggregation is a feature of Alzheimer’s disease. It is still unknown what biochemical changes occur inside the cell that could lead to Aβ42 aggregation.
Thermogenesis is associated with cellular stress, the latter of which promotes aggregation.
We perform intracellular thermometric measurements using fluorescent polymer thermometers to show that Aβ42 aggregation in living cells leads to an increase in the average cell temperature. This increase in temperature is mitigated by treatment with Aβ42 aggregation inhibitors and is independent of mitochondrial damage that may lead to thermogenesis.
In doing so, we offer a diagnostic assay that can be used to screen small molecular inhibitors for amyloid proteins under physiologically appropriate conditions. To interpret our experimental observations and to motivate the development of future models, we perform the classical molecular dynamics of the Aβ peptide model to study the factors that impede heat dissipation.
We see that this is governed by the presence of ions in its environment, the morphology of amyloid peptides, and its hydrogen-water interaction.
We show that aggregation and heat retention by Aβ peptides are good under simulated intracellular ionic conditions, which can potentially contribute to thermogenesis. The latter, in turn, triggers further nuclear events that accelerate the progression of the disease.