A new discovery could explain why we are misled about the cause of Alzheimer’s disease: ScienceAlert
Despite decades of time and billions of dollars invested in studying Alzheimer’s disease disease, aspects of its development remain stubbornly mysterious. Researchers have discovered many clues, from Gum disease to autoimmune disorders.
The original (i now controversial) The hypothesis of amyloid plaques playing a central role in the development of the condition seemed like a promising avenue to pursue, but drugs that target these plaques have provided unclear outcomes in clinical trials.
Now, using a mouse model of Alzheimer’s disease, a a team from Yale University in the US may have figured out why the protein spots seem relevant when they aren’t necessarily be directly responsible.
“We found that hundreds of axons are developing [swelling] around each amyloid deposit,” neurobiologist Peng Yuan of Yale University and colleagues they write in their work.
They discovered that the swelling was caused by a build-up lysosomes – small trash bag-like compartments created by cells to break down waste and contain it until it can be removed. These lysosomes aggregate into spheroidal structures along axons brain cells – a long ‘transmission cable’ that extends from the cell body and ends in branches of signal-sending extensions.
These swellings are thought to interfere with the ability of brain cells to conduct electrical signals that are crucial for the formation and consolidation of memories.
Using calcium and voltage imaging of individual cells, the team was able to show that the amount of signal disruption was related to the sizes of the spheroids. Spheroid swellings remain stable for a long time, so they probably continue to interfere with neuronal connectivity.
The size and number of spheroids seen in the small number of postmortem human brain samples that Yuan and colleagues were able to analyze also correlated with levels of cognitive decline. In other words, those with more severe Alzheimer’s disease had more swollen spheroids.
“Given the similarity of morphology, organelles and biochemical content [spheroids] in mice and humans, it is likely that in humans these are stable structures that could disrupt neural circuitry over longer intervals,” the researchers explain.
Yuan and the team discovered that the protein so-called PLD3 it was highly expressed in spheroids. Mice lacking the PLD3 gene did not produce the same accumulation of lysosomes and showed reduced levels of swelling in their neurons.
The team found that high levels of PLD3 occasionally lead to an increase in lysosomes even in healthy mice. However, it was more pronounced in spheroids located near amyloid plaques in mice with Alzheimer’s disease, suggesting that something about the plaques exacerbates the swelling process.
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Further research is needed to confirm these definitive links.
“It may be possible to eliminate this malfunction of electrical signals in axons by targeting PLD3 or other molecules that regulate lysosomes, independent of the presence of plaques,” explains Neuroscientist Jaime Grutzendler from Yale University.
While these findings are a source of hope, it’s still early days and researchers have already identified studies that suggest some conflicting results about how lysosomal PLD3 changes work in mice and human HeLa cells.
As we have already seen with Alzheimer’s disease, things can turn out to be more complicated again.
“We have identified a potential signature of Alzheimer’s disease that has functional consequences on brain circuits, with each spheroid having the potential to disrupt activity in hundreds of neuronal axons and thousands of interconnected neurons,” summarizes grunt dler.
This research was published in Nature.