Study finds a link between progression of Alzheimer’s disease and corpuscles in cell nuclei

Studies conducted on patients’ tissue as well as mini-brains created from stem cells have provided a better insight into Alzheimer’s disease. This disease is characterized not only by plaques that build up outside the nerve cells in the brain but also by alterations within these cells.

Study finds link between progression of Alzheimer’s disease and corpuscles in cell nuclei
Thorsten Müller (left) and David Marks have studied brain cells, including those from organoids. Image Credit: Ruhr-Universitaet-Bochum.

Scientists from the Cell Signaling research team at Ruhr-Universitaet-Bochum (RUB)’s Chair of Molecular Biochemistry led by Dr. Thorsten Müller have been investigating what exactly occurs in these cells.

The team observed that various proteins and protein components build up in cells, which also impact their activities. Furthermore, the researchers identified a link between the progression of Alzheimer’s disease and certain corpuscles in cell nuclei. The findings were published in the Acta Neuropathological Communications journal.

Aggregates seem to have a function

Alzheimer’s disease is the most prevalent form of dementia, affecting more than 50 million people. It mostly impacts individuals over the age of 65. The pathogenesis of Alzheimer’s disease in the brain is primarily defined by two factors: tau proteins and beta-amyloid plaques outside the nerve cells.

The tau protein stabilizes microtubules or tube-like structures inside cells, which are relevant for transporting nutrients in nerve cells. The protein beta-amyloid is generated in the body by the cleavage of the amyloid precursor protein (APP).

Embedded in the cell membrane of nerve cells, APP protrudes both on the outside and inside of the cells. It is usually cleaved only once close to the cell membrane. The portion within the nerve cells is not stable and thus disintegrates. In patients with Alzheimer’s disease, two cleavages occur that result in the development of three pieces.

These latest results now suggest that the part within the nerve cells is more stable in patients with Alzheimer’s disease. It contains just about 50 amino acids and can migrate into the cell nucleus along with other proteins, like TIP60 and FE65, under specific conditions. This protein complex, also called nuclear aggregates, has the ability to influence gene expression in the cell.

This suggests that the aggregates have a function in this region.”

David Marks, Study Lead Author, Cell Signaling Group, Ruhr-Universitaet-Bochum

A closer look verified this data since a protein detected within the nuclear aggregates plays a key role in DNA modification.

Two more protein candidates in cells

To understand this mechanism even better, we looked for other proteins that might be part of these aggregates and identified two more candidates involved in the nuclear aggregates, the so-called tumor suppressor proteins P53 and PML.”

David Marks, Study Lead Author, Cell Signaling Group, Ruhr-Universitaet-Bochum

In experiments on live cells, the researchers also demonstrated that nuclear aggregates created by the proteins FE65, TIP60, PML, and APP-CT50 cleave with one other over time and create relatively bigger nuclear aggregates. They also looked at brain samples collected from older deceased people as well as self-generated neuronal tissue extracted from induced pluripotent stem cells.

These mini-brains, so-called cerebral organoids, reflect the embryonic and developmental phase of a brain fairly accurately.”

Dr Thorsten Müller, Head, Cell Signaling Research Group, Chair of Molecular Biochemistry, Ruhr-Universitaet-Bochum

Almost no nuclear aggregates were observed in the comparatively young cerebral organoids, but they were detected in brain samples taken from older individuals.

This leads us to conclude that the process depends on age,” added Müller.

Striking correlation

The researchers further established on these brain samples that FE65 and APP-CT50 proteins can constitute a part of the so-called PML bodies, which exist naturally in a large proportion of cell nuclei.

Further examination of hippocampal brain slices from Alzheimer’s patients revealed a substantial association between a lower number of PML bodies in the nucleus and areas with a high beta-amyloid plaque load.

Such regions particularly indicate that APP is expressed and processed at a higher level. This may imply that the migration of FE65 and APP-CT50 proteins into the nucleus is part of the pathophysiology of Alzheimer’s disease and influences the fusion of PML bodies there.

Source:
Journal reference:

Marks, D., et al. (2021) Amyloid precursor protein elevates fusion of promyelocytic leukemia nuclear bodies in human hippocampal areas with high plaque load. Acta neuropathologica communications. doi.org/10.1186/s40478-021-01174-x.

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