Despite decades of research and billions of dollars invested in studying Alzheimer's, many aspects of the disease's development remain mysterious and elusive. Researchers have pursued various leads, from gum diseases to autoimmune disorders. The original, now-controversial hypothesis that amyloid plaques play a key role in the onset of the condition seemed like a promising pathway, yet drugs targeting these plaques have yielded unclear results in clinical trials.
Now, using a mouse model of Alzheimer's, a team from Yale University in the United States may have discovered why protein deposits appear relevant without necessarily being directly responsible. Neurobiologist Bing Yuan at Yale and his colleagues wrote in their paper: "We found that hundreds of axons develop 'swelling' around each amyloid deposit." They found that the swelling is made up of lysosomal accumulations — small compartments resembling garbage bags created by cells to break down waste and contain it until it can be removed. These lysosomes cluster into spherical structures along the axons of brain cells — the long "cable" extending from the cell body, ending in branches that transmit signals.
These swellings are believed to disrupt the ability of brain cells to transmit the electrical signals necessary for forming and consolidating memories. Using calcium and voltage imaging of individual cells, the team was able to demonstrate the extent of signal disruption associated with these spherical swellings. The spherical swellings remain stable for extended periods, making it likely that they continue to hinder neuronal connection.
The size and number of the spherical bodies observed in a small number of human brain samples post-mortem, which Yuan and colleagues were able to analyze, are also linked to levels of cognitive decline. In other words, individuals with more severe Alzheimer's had more of the swollen spherical bodies. The researchers clarify: "Given the similarities in shape, organelles, and biochemical content of the 'spherical bodies' in mice and humans, it is likely these are also stable structures in humans that could disrupt neural circuits for prolonged periods."
Yuan and his team found that a protein called PLD3 is highly expressed in the spherical bodies. Mice genetically engineered to lack the PLD3 gene did not produce the same lysosomal accumulation and exhibited lower levels of swelling in their neurons. The team found that high levels of PLD3 sometimes lead to the swelling of the lysosomes even in healthy mice. However, it was more pronounced in the spherical bodies located near amyloid plaques in mice with Alzheimer’s disease, suggesting that something about the plaques exacerbates the swelling process.
These final links require further investigation to confirm. While these findings are a hopeful introduction, they are still early, and researchers have already identified studies indicating some conflicting results in how PLD3 lysosomal changes operate in mice and human HeLa cells. As seen before with Alzheimer's, matters may once again be more complex than they appear. This research was published in the journal Nature.
