‘Toxic brain flowers’ can cause amyloid plaques

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Even today, the cellular and biomolecular mechanisms responsible for Alzheimer’s disease are still not fully understood. Scientific research over the last three decades has revealed several hypotheses, including the hypothesis of the famous “amyloid cascade”. However, treatments aimed at eliminating amyloid plaques have never shown any real effectiveness in improving neurological functions and therefore appear to “refute” the original hypothesis, suggesting that the disease is mainly due to the accumulation of these plaques. A new study joins this question, suggesting that the neuronal damage of the disease takes root inside the cells, long before the amyloid plaques form completely and clump together between the neurons. During experiments with mice, the lysosomes inside the cells had particular difficulty in securing their purifying role, and the waste accumulated there in the form of “neuronal flowers”.

According to the “amyloid cascade” hypothesis, the initial mechanism that triggers the disease is the accumulation of beta-amyloid plaques between neurons. Several risk factors (age, genetics, environment, etc.) would be involved and several series of inflammatory mechanisms would subsequently be triggered. These processes will then overly activate the Tau protein, which in turn accumulates between the neurons, preventing internuronal communication, leading to their degeneration and death.

These reaction sequences would then cause the cognitive deficits observed in Alzheimer’s disease (including memory loss). They would also be the cause of brain damage, which is already visible more than a decade before the first symptoms.

However, this hypothesis has never been unanimously accepted by scientists, especially after the observed lack of effectiveness of “anti-plaque therapies”. In particular, they may not relieve patients’ dementia, suggesting that they may not be the best therapeutic targets for treating the disease.

The new study, led by New York’s Langone Medical University and the Nathan Kline Institute for Psychiatric Research, also challenges the famous assumption. For the first time, the neuronal damage typical of Alzheimer’s has been linked to dysfunctions of lysosomes inside cells where beta-amyloid plaques are first thought to appear.

Previously, the mechanism hypothesis primarily attributed the damage seen in Alzheimer’s disease to what happens after amyloid builds up outside brain cells, not before and inside neurons. “, Explains in a press release Ju-Hyun Lee, principal investigator of the new study and assistant research professor at the Department of Psychiatry in Langone, and also researcher at the Nathan Kline Institute.

“Poisonous flowers” inside neurons

In their new study, New York researchers observed cellular dysfunctions in mice that had been induced with Alzheimer’s disease. In particular, they followed the decrease in acid activity within the lysosomes as the disease progressed and cell lesions developed. Lysosomes play a role in the elimination of waste in cells (metabolically or from the cells themselves), by secreting an acid enzyme that breaks them down.

Imaging observations then showed that as the neurons degenerated, the lysosomes lost their efficiency by fusing with other vacuoles. These so-called “autophagic” vacuoles have the task of removing excess cellular constituents and are thus more or less already saturated with waste products, including previous forms of beta-amyloid.

In the most damaged and dying neurons, these fused vacuoles clumped together to form flower-like patterns, swell and cluster around the nucleus of the cell: hence their name “flowers”. toxic. These rosette patterns have also already been observed in the brain cells of three patients who died of Alzheimer’s disease.

In addition, the researchers found that accumulations of beta-amyloid proteins also formed filaments inside diseased neurons. The results, published in the journal Nature Neurosciencethen assume that the neuronal degeneration associated with Alzheimer’s would take root inside the cells, rather than outside (as the amyloid cascade hypothesis assumes), and this before the amyloid plaques do not accumulate in the brain.

A new therapeutic path

This new study changes our basic understanding of the development of Alzheimer’s disease says Ralph Nixon, also lead researcher on the study, professor in the Department of Psychiatry and Cell Biology at Langone and director of the research center for dementia at Nathan Kline. According to the expert, the discovery could explain why so many experimental therapies designed to remove amyloid plaques have not stopped The development of the disease.Brain cells would already be paralyzed before plaques form completely outside the neurons.

Research also suggests that control of lysosomal functions may be a better therapeutic target. The latter could in particular focus on reversing lysosomal dysfunction and restoring acid levels in neurons. Another study from Langone University would have identified the gene responsible for the problem of eliminating cellular waste.

However, so far the research has only focused on mice, and the mechanisms may be completely different in humans. Therefore, more studies are needed before it can be said that this new hypothesis overrides the hypothesis of the amyloid cascade.

Source: Nature Neuroscience

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