Despite decades of time and billions of dollars being invested in the study of Alzheimer’s disease, some aspects of its development remain surprising. Researchers have pursued many mechanisms, from gum disease to autoimmune diseases.
The original (and now controversial) hypothesis of amyloid plaques playing a major role in the manifestation of this condition seems to be a promising approach to follow, but drugs that target these plaques have yielded inconclusive results in clinical trials.
Now, using a mouse model of Alzheimer’s disease, a a team from Yale University in the US may have found the reason why proteins appear to be important for no reason to be directly responsible.
“We found that hundreds of axons grow [swelling] around each amyloid layer,” Yale University neuroscientist Peng Yuan and colleagues write in their paper.
They found that inflammation is caused by lysosomes – tiny bin-bag compartments that are made by cells to break down waste and hold it until it is removed. These lysosomes enter the clusters surrounding the axons of brain cells – the long “transmitter cable” that leaves the cell body, and terminates in signal-transmitting branches.
This inflammation is thought to interfere with the brain’s ability to conduct electrical signals that are essential for forming and consolidating memories.
Using calcium and electrical imaging of each type of cell, the team was able to show how much signal disruption is associated with spheroid growth. The swelling of the spheroid remains stable for a long time, thus continuing to disrupt neuron connectivity.
The size and number of spheroids seen in the few sections of postmortem brains that Yuan and colleagues were able to analyze also correlate with cognitive decline. In other words, those with more severe Alzheimer’s disease had more swollen spheroids.
“Based on the similarity of morphology, organelle and biochemical content [spheroids] in mice and humans, it is possible that, in humans, these are also stable factors that can disrupt neural circuits in the long term,” the researchers explain.
Yuan and team found that a protein called PLD3 was highly expressed in the spheroids. Mice engineered to lack the PLD3 gene did not develop lysosome buildup, and showed reduced inflammation in their neurons.
The team found that increased levels of PLD3 sometimes lead to lysosome enlargement even in healthy mice. However, it is more visible in the spheroids around the amyloid plaques in mice with Alzheimer’s, which suggests that some of the plaques increase inflammation.
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These latter links require further investigation to confirm.
“It may be possible to eliminate the breakdown of electrical signals in axons by targeting PLD3 or other molecules that regulate lysosomes, independent of the presence of markers,” says Jaime Grutzendler, neuroscientist at Yale University.
Although these findings are promising, it is still early days and researchers have already found studies showing conflicting results on how PLD3 lysosome mutations work in mice and human HeLa cells.
As we have already seen with Alzheimer’s, things can be much more complicated, however.
“We have identified an Alzheimer’s signature that can work around the brain, where each spheroid can disrupt hundreds of axons and thousands of interconnected neurons,” summarizes Grutzendler.
This study was published in Nature.