Small clusters of proteins, so-called Aβ oligomers, are the main suspects for the development of Alzheimer’s disease. However, it is still unclear where and under what conditions the harmful clumping occurs. Researchers from Heinrich Heine University in Düsseldorf and the Jülich Research Center, together with partners from Cologne University and University Hospital, have now found that a slightly acidic environment is conducive to development. The oligomers form in it around 8,000 times faster than at a neutral pH value, as the researchers write in the journal Nature Communications . Such a slightly lowered pH value can be found in certain substructures of nerve cells.
The exact causes of Alzheimer’s dementia are still not fully understood despite intensive research. For decades, the focus was on characteristic protein deposits, which are easily visible with the microscope and can be detected in the brain of the sick. Today, however, researchers are primarily focusing on their “smaller relatives”, the oligomers. These are also agglomerations of the peptide amyloid-beta (Aβ), albeit of a significantly smaller extent, which typically consist of only a few units.
Aβ is not harmful in itself and also occurs in healthy people. It tends to assemble into harmful structures, for example when metabolic processes in the brain are disturbed. The biochemical processes that trigger these toxic oligomers are considered to be the triggers of Alzheimer’s dementia. However, it is unclear where and how these oligomers are formed. Up until now, the process could not be realistically reproduced in the test tube. This is because the amounts of Aβ required for this are far greater than the amounts that have been detected in the cerebral fluid.
In the work that has now been published, the researchers have now been able to show that the formation of the oligomers is highly dependent on the pH value. Under slightly acidic conditions, they form 8,000 times faster than at neutral pH. Such a pH value is found in certain substructures of the cells, the endosomes and lysosomes: small vesicles or vesicles that play a central role in the transport and breakdown of substances in the cell.
“The Aβ quantities found in these cell areas are thus sufficient to enable the Aβ oligomers to form,” explains Wolfgang Hoyer from the Heinrich Heine University in Düsseldorf and the Jülich Research Center.
Endosomes and lysosomes have long been the focus of Alzheimer’s research. These are the places where individual Aβ molecules arise in the first place through the breakdown of a precursor protein. And there are collection points to which the Aβ taken up by the cell is transported. “Our results now suggest that endosomes and lysosomes are actually the places where Aβ oligomers are preferentially formed,” says Wolfgang Hoyer.
Study provides explanations for protein maldistribution
The researchers were also able to link the defective Aβ oligomers with another characteristic of Alzheimer’s disease: after adding the Aβ oligomers, they observed a faulty distribution of the tau protein within the nerve cells. The tau protein is a second protein closely linked to the progression of Alzheimer’s disease. The occurrence in the wrong places can lead to disturbances in the activity and structure of nerve cells.
“The maldistribution and other pathological changes in tau are decisive for the loss of function of the nerve cells and the cognitive limitations in Alzheimer’s patients. The fact that the Aβ oligomers described here can induce this pathological change in the tau protein in nerve cells shows the high pathophysiological relevance of the study, ”explains Hans Zempel from Cologne University Hospital.
The research team also examined the size and shape of the oligomers using cryo-electron microscopy and atomic force microscopy. “The knowledge gained creates a basis for better deciphering the special properties and effects of these critical protein aggregates,” explains Wolfgang Hoyer. This is helpful for developing diagnostic and therapeutic strategies that specifically target oligomers.
Featured image: Small Aβ oligomers (left: cryo-electron microscopy) are clumps made up of a few Aβ molecules. They attach to each other to form short, worm-like structures called protofibrils (right: atomic force microscopy). In an acidic environment, Aβ oligomers form very quickly and clump together to form large particles, from which protofibrils detach after the pH value has been neutralized (right, red arrows). Copyright: Research Center Jülich, HHU Düsseldorf / Wolfgang Hoyer
Marie P. Schützmann, Filip Hasecke, Sarah Bachmann, Mara Zielinski, Sebastian Hänsch, Gunnar F. Schröder, Hans Zempel, Wolfgang Hoyer
Endo-lysosomal Aβ concentration and pH trigger formation of Aβ oligomers that potently induce Tau missorting
Nat Commun 12, 4634 ( 2021), DOI: 10.1038 / s41467-021-24900-4
Provided by Julich