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Despite decades of research devoted to Alzheimer’s disease, we are still far from having identified the exact biomolecular mechanisms, which turned out to be much more complex than we thought. Over the past five years, this complexity has called into question the famous “amyloid cascade theory”, which has become increasingly controversial as treatments based on it show little efficacy. Recently, Yale researchers discovered that the dementia caused by the disease could be caused by a “swelling” of the axons, caused by an accumulation of lysosomes (cell organelles) around the amyloid plaques. Will this discovery finally provide a better lead to treat the disease?
For a long time, it was widely accepted that the main cause of Alzheimer’s disease was the accumulation of amyloid plaques in neurons. However, research has recently revealed that this accumulation is only one of the hallmarks of the disease, and therefore many other mechanisms have yet to be discovered. In question, some researchers have incriminated autoimmune diseases, while others have suggested that the symptoms of the disease are rather caused by the decrease in the soluble form of amyloid protein.
Moreover, in view of the low effectiveness of currently available treatments, scientists are forced to turn to other avenues in the hope of developing potentially more suitable treatments. Most of the approved treatments focus in particular on the removal of amyloid plaques. And despite their ability to reduce accumulation, symptoms of dementia ameliorate little or not at all in patients with the disease.
The new study, detailed in the journal Nature, suggests that the accumulation of lysosomes — the organelles responsible for dissolving cellular waste — may be the cause of the symptoms of Alzheimer’s dementia. Another one study has in fact already evoked a more or less similar theory, according to which lysosomes would become incapable of properly digesting cellular waste, which accumulates and swells in patients. This study also suggested that by “blowing up” from the overload, these lysosomes eventually burst, releasing toxic compounds that kill the cell as well as amyloid proteins, which accumulate and solidify.
Yale researchers suggest on the other hand that these lysosomal swellings, detected around areas of amyloid plaque accumulation, impede the flow of electrical signals through neurons, which leads to dementia. ” We have identified a potential signature of Alzheimer’s disease that has functional implications for brain circuitry, with each spheroid having the potential to disrupt the activity of hundreds of neural 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 was previously induced, the researchers found that the formation of each amyloid plaque was surrounded by an accumulation of small spherical grains along the axons, which were abnormally swollen. These grains were notably composed of lysosomes, which as they accumulate, prevent the circulation of electrical signals at the level of the axons.
Using a cellular imaging technique, the researchers demonstrated that the disruption of interneuron electrical signals was strongly linked to the size of the granules accumulated along the axons. The number of these spheroids would also be involved, according to postmortem analysis of the brains of patients with Alzheimer’s disease, and each spheroid would disrupt the connection between thousands of neurons.
Yale researchers also found that a protein called PLD3 induces the 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 neuronal functions of the latter were also significantly improved.
Moreover, high levels of PLD3 would induce excessive accumulation of lysosomes and hypertrophy of axons, even in healthy mice. Thereby, ” it might 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 “Said Jaime Grutzendler, professor of neurology and neuroscience at Yale and lead author of the study.
However, the hypertrophy of lysosomes is all the same more important near the amyloid plaques. Therapeutic targeting of PLD3 could thus be a promising avenue for potentially effective treatments, as well as tools for early diagnosis. But further research is still needed before the involvement of PLD3 in the disease can be confirmed.