Summary: The heat from amyloid-beta buildup may cause healthy amyloid beta to pool, causing more and more aggregates to form. However, with the addition of a new drug compound, the accumulation of amyloid-beta could be stopped and the cell temperature lowered.
source: Cambridge University
Researchers have shown that a buildup of amyloid beta, one of the two key proteins implicated in Alzheimer’s disease, causes cells to overheat and “fry like eggs.”
The researchers, from the University of Cambridge, used sensors small and sensitive enough to detect temperature changes within individual cells, and found that as amyloid-beta imbalances and clumps together, it causes the cells to overheat.
In an experiment using human cell lines, researchers found that the heat released from amyloid-beta buildup can cause healthy amyloid beta to build up, causing more and more aggregates to form.
In the same series of experiments, the researchers also showed that amyloid-beta buildup could be stopped, and cell temperature lowered, with the addition of a drug compound. Trials also indicate that the compound has potential as a treatment for Alzheimer’s disease, although extensive testing and clinical trials will be required first.
The researchers say their test could be used as a diagnostic tool for Alzheimer’s disease, or to screen for potential candidate drugs.
The results are reported in Journal of the American Chemical Society.
Alzheimer’s disease affects an estimated 44 million people worldwide, and there are currently no effective diagnoses or treatments. In Alzheimer’s disease, beta-amyloid and another protein called tau builds up into tangles and plaques–collectively known as tangles–causing brain cells to die and the brain to shrink. This results in memory loss, personality changes, and difficulty performing daily functions.
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. It is still unknown what kind of biochemical changes within the cell lead to the accumulation of amyloid-beta.
In the research group of Professor Gabriel Kaminski-Shirl in the Department of Chemical Engineering and Biotechnology at the University of Cambridge, they were studying the possible link between temperature and the accumulation of amyloid-beta in human cells.
The field of study of temperature changes inside a cell is known as intracellular thermogenesis. It’s a new and challenging field: Scientists have developed sensors that can measure temperature changes, however, no one has attempted to use these sensors to study conditions like Alzheimer’s disease.
“Thermogenesis has been associated with cellular stress, which may promote further accumulation,” said Chi Wei-chung, first author of the study. “We think that when there is an imbalance in the cells, such as when the concentration of amyloid-beta is a little high and it starts to build up, the cellular temperatures increase.”
“A cell warming is like frying an egg — as it gets hot, the proteins begin to clump together and become nonfunctional,” said Sherrill Kaminsky, who led the research.
The researchers used small temperature sensors called fluorescent polymer thermometers (FTPs) to study the association between aggregation and temperature. They added amyloid-beta to human cell lines to start the assembly process and used a chemical called FCCP as a control, as it is known to induce an increase in temperature.
They found that when beta-amyloid began to form thread-like aggregates called fibrils, the cells’ average temperature began to rise. The increase in cellular temperature was significant compared to cells to which no amyloid-beta protein was added.
“When the fibers begin to elongate, they release energy in the form of heat,” said Sherrill Kaminsky. “Amyloid-beta assembly requires a lot of energy to get started, but once the assembly process starts, it speeds up and releases more heat, allowing more aggregates to form.”
“Once the clumps form, they can exit the cell and be picked up by neighboring cells, infecting healthy amyloid-beta in those cells,” Chung said. “No one has shown this correlation between temperature and aggregation in living cells before.”
Using a drug that inhibits beta-amyloid buildup, the researchers were able to pinpoint the fibers as the cause of thermogenesis. It was not previously known whether protein buildup or potential damage to mitochondria – the ‘batteries’ with which cells operate – was responsible for this phenomenon.
The researchers also found that cellular elevated temperatures can be mitigated by treating them with aggregation inhibitors, highlighting its potential as a treatment for Alzheimer’s disease.
Laboratory experiments were supplemented by computational modeling describing what might happen to beta-amyloid in an intracellular environment and why it might lead to increased intracellular temperatures. The researchers hope their work will stimulate new studies that include different criteria of physiological significance.
Financing: The research was supported in part by Alzheimer’s Research UK, the Cambridge Trust, Wellcome and the Medical Research Council, part of UKRI Research and Innovation (UKRI).
About this research on Alzheimer’s disease news
author: Sarah Collins
source: Cambridge University
Contact: Sarah Collins – University of Cambridge
picture: The image is attributed to Chyi Wei Chung
original search: open access.
“Intracellular assembly of Aβ42 leads to cellular thermogenesis” by Chyi Wei Chung et al. Journal of the American Chemical Society
Intracellular assembly of Aβ42 leads to cellular thermogenesis
Aβ42 accumulation is a hallmark of Alzheimer’s disease. It is still unknown what biochemical changes within the cell will eventually lead to the accumulation of Aβ42.
Thermogenesis has been associated with cellular stress, the latter of which may enhance aggregation.
We perform intracellular thermometry measurements using fluorescent polymer thermometers to show that Aβ42 accumulation in living cells leads to an increase in cell mean temperatures. This temperature rise is attenuated upon treatment with an accumulation inhibitor of Aβ42 and is independent of mitochondrial damage that could otherwise lead to thermogenesis.
By this, we present a diagnostic assay that can be used to screen for small molecule inhibitors of amyloid proteins in physiologically relevant settings. To explain our experimental observations and stimulate future model development, we perform a classic molecular dynamics model of Aβ peptides to examine factors that impede heat dissipation.
We note that this is controlled by the presence of ions in the surrounding environment, the morphology of amyloid peptides, and the extent of hydrogen bonding interactions with water.
We show that assembly and heat retention by Aβ peptides is preferred under intracellular ionic conditions, which can enhance thermogenesis. The latter, in turn, will lead to further nucleation events that accelerate disease progression.