Despite the decades and billions of dollars invested in the study of Alzheimer’s disease, some aspects of its development remain stubbornly mysterious. Researchers have followed many leads, from gum disease to autoimmune diseases.
The original (and now controversial) hypothesis that amyloid plaques play a central role in disease emergence seemed like a promising way forward, but drugs targeting these plaques have provided unclear results 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 protein patches seem relevant without necessarily being directly responsible.
“We found that hundreds of axons grow [swelling] around each amyloid deposit,” Peng Yuan, a neurobiologist at Yale University, and colleagues write in their paper.
They found that the swelling is formed by a buildup of lysosomes – small garbage bag-like compartments created by cells to break down waste and contain it until it can be removed. These lysosomes clump together into spheroidal structures along the axons of brain cells – the long “transmission cable” that extends from the cell body and ends in branches of signal-sending extensions.
These swellings are thought to disrupt the abilities of brain cells to conduct electrical signals that are vital for forming and consolidating memories.
Using calcium and voltage imaging of single cells, the team was able to show that the amount of signal disruption was related to the size of the spheroids. The spheroid swellings remain stable for long periods of time, thus likely continuing to disrupt neuron connectivity.
The size and number of spheroids observed in a small number of post-mortem human brain samples that Yuan and his colleagues were able to analyze were also correlated with levels of cognitive decline. In other words, people with more severe Alzheimer’s disease had more swollen spheroids.
“Given the similarity in morphology, organelles and biochemical content of [spheroids] in mice and humans, it is likely that in humans they are also stable structures that could disrupt neural circuitry for prolonged intervals,” the researchers explain.
Yuan and his team found that a protein called PLD3 was highly expressed in spheroids. Mice engineered to lack 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 sometimes led to lysosome enlargement, even in healthy mice. However, it was more pronounced in spheroids located near amyloid plaques in mice with Alzheimer’s disease, suggesting that something in the plaques is exacerbating the swelling process.
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These latter links require further investigation to be confirmed.
“It may be possible to eliminate this degradation of electrical signals in axons by targeting PLD3 or other molecules that regulate lysosomes, independent of the presence of plaques,” says Jaime Grutzendler, a neuroscientist at Yale University. .
While these findings are a hopeful lead, it is still in its infancy and researchers have already identified studies suggesting conflicting results on how PLD3 lysosome modifications work in mice and HeLa cells. human.
As we have already seen with Alzheimer’s disease, things can get even more complicated, again.
“We have identified a potential signature of Alzheimer’s disease that has functional repercussions on brain circuitry, with each spheroid having the potential to disrupt the activity of hundreds of neuronal axons and thousands of interconnected neurons,” summarizes Grutzendler.
This research was published in Nature.
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