In the brains of people with Alzheimer’s disease and some other types of dementia, two proteins called beta-amyloid and tau begin to misbehave in different ways — although it’s unclear whether these abnormalities are drivers of the disease or consequences of it.
With tau, the protein begins to fold into an incorrect shape and comes together into threads called fibrils inside brain cells, ultimately killing those cells. A long-standing question is how this misfolding spreads throughout the brain.
Today, thanks to a study published in PNAS According to researchers at Northwestern University and the University of California, Santa Barbara, we may have an answer.
The study team determined that tau proteins with certain mutations are more vulnerable to misfolding and that there is a certain “hot spot” on these proteins that can connect them together. The hot spot repels water but is still covered by it, and when this water is released, the proteins come together in the form of stiff fibrils.
“You have a certain site and water can’t really cover it because it doesn’t like water,” says Songi Han, a physical chemist at Northwestern University. “But this part still needs to be protected, because if you don’t, the protein collapses and is no longer available.”
“What water tends to do is build a stabilizing cap around itself and basically these caps of water attract each other.”
The researchers studied a model of a mutated tau fragment made up of 19 amino acids, combining laboratory tests with computer modeling to understand how the proteins might go from initially soft and shapeless to stiff and stacked as fibrils.
Through a docking method that takes place in stages – with the first stage at the water-covered hot spot – there is a release of energy which is then used to recruit new tau and trigger the misfolding process.
“Proteins have to misfold and stack neatly into fibrils to elongate while propagating the same misfolded shape, and the only way for this process to be eternal is if the same site on the protein stacks on the same site,” says Han.
“If you have a small mismatch in the alignment of the tau forms that stack up to the end of the fibril, the structure will eventually stop growing.”
Further tests showed that when the hot spot was covered with a chemical label, the fibrils stopped growing. Although the research is still in its early stages, there is potential here for drugs that can target this docking point and prevent connections from being made.
If left unchecked, when cells containing tau fibrils die, these fibrils are released to then start the process in other neurons, so the problem spreads throughout the brain.
“Once you know that aggregation-prone tau proteins always have a hot spot that is first attracted to the same site of tau that is stacked on the fibrils, then you know that there is always a part of the protein that you can target to neutralize it,” says Han.
“If you know where to block its misfolding action, you could block it to prevent it from spreading.”
One idea the researchers have suggested is creating synthetic tau fibrils that could be used to study the progression of Alzheimer’s disease and dementia more generally. A better understanding of how fibrils form will be crucial for creating artificial versions.
The study of abnormal tau proteins and beta-amyloid proteins currently poses a real challenge for researchers: penetrating the brain of a living patient is incredibly difficult to achieve, and in post-mortem brains donated to science, all dementia processes have stopped.
“To cure a disease, you have to be able to recreate it,” Han explains. “There’s a real problem that disease-mimicking tau fibrils can’t be synthesized easily. It’s really difficult to try to do any development with human patient tissue.”
“We try to give the principle of how it works so that others can find better, faster and more rational solutions.”
The research was published in PNAS.
This article was fact-checked by Fiona MacDonald and edited by Fiona MacDonald. Although we are proud of our process, we are only human. If you spot an error, please let us know.
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