The real cause of Alzheimer’s finally discovered?

Despite decades of research devoted to Alzheimer’s disease, we are still far from defining the exact biomolecular mechanisms, which turn out to be much more complex than we thought. Over the past five years, this complication has raised questions about the famous “amyloid cascade theory,” which has become increasingly controversial because treatments based on it show little efficacy. Yale University researchers recently discovered that dementia from the disease could be caused by a “swelling” of axons, caused by the buildup of lysosomes (cell organelles) around amyloid plaques. Will this discovery finally provide a better motive for treating the disease?

For a long time, it was widely accepted that the main cause of Alzheimer’s disease is the buildup of amyloid plaques in nerve cells. However, recent research has revealed that this accumulation is only one of the hallmarks of the disease, and thus many other mechanisms have yet to be discovered. In question, some researchers have blamed autoimmune diseases, while others have suggested that the symptoms of the disease are rather caused by it Decrease in the form of the soluble amyloid protein.

Moreover, due to the low efficacy of currently available treatments, scientists are forced to turn to other methods in hopes of developing more appropriate treatments. Most approved treatments focus specifically on removing amyloid plaques. Despite its ability to reduce buildup, dementia symptoms improve little or not at all in patients with this disease.

The new study is detailed in the journal nature, suggests that a buildup of lysosomes — the organelles responsible for dissolving cellular waste — may be a cause of Alzheimer’s dementia symptoms. other study He has already raised a somewhat similar theory, according to which lysosomes become unable to properly digest cellular waste, which builds up and swells in patients. This study also suggested that by “bursting” from overload, these particles eventually explode, releasing toxic compounds that kill the cell as well as amyloid proteins, which accumulate and harden.

On the other hand, the Yale researchers suggest that these lysosomal bulges, which are detected around areas of accumulation of amyloid plaques, impede the flow of electrical signals through neurons, leading to dementia. ” We have identified a potential signature of Alzheimer’s disease that has functional implications for brain circuitry, as each spheroid has the potential to disrupt the activity of hundreds of axons and thousands of interconnected neurons. », Explain The authors of the new study.

Swelling caused by a specific biomarker

Using a mouse model where Alzheimer’s disease had previously been induced, the researchers found that each amyloid plaque formation was surrounded by an accumulation of small spherical granules along the axons, which were abnormally swollen. These grains were remarkably composed of lysosomes, which accumulate preventing the rotation of electrical signals at the level of axons.

Using cellular imaging technology, the researchers showed that the perturbation of internal electrical signals is strongly related to the size of granules accumulated along the axons. The number of these spheroids would also be implicated, according to a post-mortem analysis of the brains of Alzheimer’s patients, and each spheroid would disrupt communication between thousands of neurons.

The Yale researchers also found that a protein called PLD3 induces growth and clumping of lysosomes, causing widespread swelling of axons. By genetically modifying mice to remove the biomarker, they found a significant reduction in axonal swelling in diseased mice. The neurological functions of the latter are also significantly improved.

Moreover, high levels of PLD3 may lead to excessive accumulation of lysosomes and atrophy of axons, even in healthy mice. And therefore , ” It may be possible to eliminate this degradation of electrical signals in axons by targeting PLD3 or other molecules that regulate lysosomes, regardless of the presence of plaques. Said Jaime Grotzendler, professor of neuroscience and neuroscience at Yale University and lead author of the study.

However, lysosome hyperplasia is more significant near amyloid plaques. Therapeutic targeting of PLD3 could thus be a promising avenue for potentially effective therapies, as well as early diagnostic tools. But more research is still needed before the involvement of PLD3 in the disease can be confirmed.

source : nature