Alzheimer's disease is the most frequent cause of dementia; if we are to reduce its impact, we must learn as much as possible about how it begins and the impacts it has on brain cells - and a recent study suggests that the illness's progression can lead cells to overheat dangerously.
We know that the proteins amyloid-beta and tau cluster together in the brain, destroying cells and causing the brain to atrophy in Alzheimer's disease. The new study shows how amyloid-beta can destroy a cell "like frying an egg" by raising its temperature.
The fact that we don't fully understand what causes amyloid-beta to build up in the brain is one of the most difficult aspects of Alzheimer's research; however, in this latest study, researchers were able to observe it triggering this temperature change, known technically as intracellular thermogenesis.
"Once the aggregates have formed, they can exit the cell and be taken up by neighboring cells, infecting healthy amyloid-beta in those cells," says University of Cambridge chemical engineer Chyi Wei Chung.
Alzheimer's disease is famously difficult to research because it takes a long time to develop; the entire impact on a person's brain can only be investigated in depth after death by studying brain tissue.
Fluorescent polymeric thermometers, which are small temperature sensors, were used in this investigation (FPTs).
To start the aggregation process, the researchers introduced amyloid-beta to human cell lines in the lab. The average temperature of the cells began to climb after the amyloid-beta protein began to form threads known as fibrils, compared to cells that had not had any of the protein artificially added. This sets off a chain reaction.
"As the fibrils start elongating, they release energy in the form of heat," explains University of Cambridge neuroscientist 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."
The researchers were able to isolate and identify fibril formation as the origin of thermogenesis by suppressing amyloid-beta aggregation in other cells. Future Alzheimer's therapies might focus on avoiding aggregation as a strategy to keep brain cells cold and, most importantly, alive.
"We show, for the first time in live cells, that Aβ42 [amyloid-beta subvariant 42] elongation is directly responsible for elevating cell-averaged temperatures," the team states.
In addition to laboratory tests, computer models were employed to analyze how amyloid-beta could act within a cell to raise temperatures, perhaps getting us closer to a complete understanding of the illness that affects tens of millions of people.
Treatments based on the findings are still a long way off, but the research sheds light on one of the disease's riddles. It was previously considered that damage to the cell batteries or mitochondria was causing thermogenesis.
"Thermogenesis has been associated with cellular stress, which may promote further aggregation," Chung explains.
"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."
