In brains of people with Alzheimer’s and certain other types of dementia, two proteins called amyloid-beta and tau start misbehaving in different ways.
Not clear if these abnormalities are drivers of disease, or consequences of it, tau protein begins to misfold into wrong shape, collecting in fibrils inside brain cells. Eventually killing those cells off, long-standing question has been how this misfolding spreads through brain, offering hope for better understanding and treatment.
New Study In PNAS From Northwestern And UCSB
Thanks to study published in PNAS from researchers at Northwestern University and University of California Santa Barbara, we may have answer encouragingly.
Study team determined tau proteins with certain mutations more vulnerable to misfolding, and there is certain hotspot on these proteins connecting them together.
Hotspot repels water but still capped by it, and when that water released, proteins join together in rigid fibril shape spreading problem.
Water Cap Attracts And Triggers Misfolding
You have certain site, and water cannot quite coat it because it does not like water, says physical chemist Songi Han from Northwestern University. But that part still needs to be protected, because if you do not, then protein crashes out and is no longer available for normal function.
What water tends to do is build stabilizing cap around it and basically these water caps attract each other, bringing proteins together.
19 Amino Acids Fragment Model Studied
Researchers studied fragment model of mutated tau made up of 19 amino acids, combining lab tests with computer modeling to figure transition. Via docking method that happens in stages, with first stage at water-capped hotspot, there is release of energy used to recruit new tau and trigger misfolding.
Proteins have to misfold and neatly stack to fibrils to elongate while propagating same misfolded shape, and only way process forever is same site stacking same, Han said.
If you have tiny mismatch in alignment of tau shapes that stack to fibril end, structure will eventually stop growing, halting propagation and spread.
Chemical Tag Stops Growth Offering Drug Potential
Further tests showed when hotspot covered by chemical tag, fibrils stopped growing, while still very early days for research, potential for drugs targeting docking point.
Left unchecked, when cells holding tau fibrils die off, those fibrils released to then start process in other neurons, so problem spreads through brain progressively.
Once you know aggregation-prone tau proteins always have hotspot first attracted to same site of tau stacked to fibrils, then you know always some part to target neutralize, Han said. If you know where to block its action of misfolding, you could block it to prevent it from propagating, offering promising therapeutic strategy for future.
Synthetic Tau Fibrils For Better Research
One of ideas suggested by researchers is creating synthetic tau fibrils that could be used to study progression of Alzheimer’s and dementia more generally.
Better understanding of how fibrils form will be crucial to making artificial versions, studying abnormal tau and amyloid-beta proteins at moment real challenge for researchers.
Getting inside brain of living patient incredibly difficult to do, and in post-mortem brains donated to science all dementia processes have stopped already. In order to cure disease, one needs to be able to recreate it, says Han, real problem that disease-mimicking tau fibrils cannot be synthetically made easily. It really difficult to try to do any development with human patient tissue, we are trying to give principle of how it works so others can find solutions better.
Q&A
Q: How may water be hidden trigger behind spread of Alzheimer’s tau misfolding in brain according to PNAS study?
A: Study found tau hotspot repels water but capped by it, when water released proteins join in rigid fibril shape, energy release recruits new tau triggering misfolding spread.
Q: What did Northwestern physical chemist Songi Han say about water caps attracting each other driving tau fibrils growth?
A: Han said you have site water cannot quite coat because it does not like water, water builds stabilizing cap around it, water caps attract each other causing aggregation.
Q: Could blocking hotspot with chemical tag stop tau fibrils from growing and offer new Alzheimer’s drug target?
A: Tests showed when hotspot covered by chemical tag fibrils stopped growing, suggesting potential for drugs aiming at docking point to stop connections and prevent propagation spreading.
FAQ
Q: What are amyloid-beta and tau proteins doing in brains of people with Alzheimer’s and other dementias?
A: Two proteins misbehaving, tau begins to misfold into wrong shape, collects together in threads called fibrils inside brain cells, eventually killing cells and spreading.
Q: How did researchers study 19 amino acids fragment model of mutated tau combining lab tests and computer modeling?
A: Researchers studied fragment model combining lab tests with computer modeling to figure how proteins go from soft shapeless initially to rigid stacked as fibrils via staged docking.
Q: Why is creating synthetic tau fibrils important for studying Alzheimer’s and developing treatments according to researchers?
A: Creating synthetic fibrils could be used to study progression more generally, better understanding how fibrils form crucial to making artificial versions, curing disease requires ability to recreate it.
Q: Why is studying abnormal tau and amyloid-beta proteins currently real challenge for researchers in living patients?
A: Getting inside brain of living patient incredibly difficult, and in post-mortem brains donated to science all dementia processes have stopped, making development with human tissue really difficult.
Q: How does tiny mismatch in alignment affect tau fibril growth and what does that mean for propagation?
A: If tiny mismatch in alignment of tau shapes that stack to fibril end, structure will eventually stop growing, meaning same site must stack to same for forever propagation.
Disclaimer: This article provides educational information based on study published in PNAS by Northwestern University and University of California Santa Barbara researchers and does not constitute professional medical advice, diagnosis, or treatment.
