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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 past three decades has revealed many hypotheses, including the famous “amyloid cascade”. However, treatments aimed at eliminating amyloid plaques have never shown any real efficacy in improving neurological function, and thus appear to “disprove” the initial hypothesis that the disease is primarily due to plaque buildup. A new study joins this interrogation, suggesting that the disease’s neuronal damage takes root within cells, long before amyloid plaques fully form and clump together between neurons. During tests in mice, intracellular lysosomes had particular difficulty ensuring their purifying role, and wastes accumulated there in the form of “neural blooms”.
According to the ‘amyloid cascade’ hypothesis, the primary mechanism for triggering the disease is the accumulation of beta-amyloid plaques between neurons. Many risk factors (age, genetics, environment, etc.) will be involved and subsequently many mechanisms of inflammation will be triggered. These processes will then over-activate the tau protein, which, in turn, accumulates between neurons, impairing communication between neurons leading to their degeneration and death.
These sequences of interactions may cause the cognitive deficits observed in Alzheimer’s disease (including memory loss). They may also be the cause of brain damage, which has already appeared more than a decade before the first symptoms appear.
However, this hypothesis has never been unanimously accepted by scientists, especially after the notable lack of efficacy of “anti-plaque treatments”. In particular, they cannot alleviate dementia in patients, suggesting that they may not be the best therapeutic targets for treating the disease.
The new study, led by New York’s Medical University Langone and the Nathan Klein Institute for Psychiatry Research, also challenges a famous assumption. For the first time, neuronal damage typical of Alzheimer’s disease has been linked to a defect in intracellular particles, in which beta-amyloid plaques are thought to appear for the first time.
” Previously, the mechanism hypothesis had attributed the damage observed in Alzheimer’s disease to what occurs after amyloid accumulates outside brain cells, rather than before and within neurons. Ju-Hyun Lee, principal investigator on the new study and associate research professor in the Department of Psychiatry at Langone, who is also a researcher at the Nathan Kline Institute, explains in a press release.
“Toxic flowers” inside neurons
In their new study, researchers in New York observed cellular disruption in mice with Alzheimer’s disease. In particular, they followed a decrease in acid activity within the lysosomes, as the disease progressed and cellular lesions developed. Lysosomes play a role in the elimination of waste products in cells (metabolic or from the cells themselves), by secreting an acidic enzyme that breaks them down.
Then imaging observations showed that as the neurons deteriorated, the lysosomes lost their efficacy by merging with other vacuoles. These so-called “phagocytic” vacuoles have a role in eliminating excess cellular components and are thus already saturated with waste residues, including earlier forms of beta-amyloid.
In the most damaged and dying neurons, these fused vacuoles clump together to form flower-like patterns, swell and cluster around the cell nucleus: hence the name ‘poisonous’ flowers. These pinkish patterns have 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 within diseased neurons. The results are published in the journal natural neurosciencethen hypothesized that the neurodegeneration associated with Alzheimer’s disease would take root within cells, rather than outside them (as the amyloid cascade hypothesis assumes), and this is before amyloid plaques no longer accumulate in the brain.
A new treatment path
” This new study changes our basic understanding of the development of Alzheimer’s disease Says Ralph Nixon, who is also the study’s principal investigator, professor in the Department of Psychiatry and Cell Biology at Langone and director of the Nathan Klein Dementia Research Center. According to the expert, this finding could explain why many experimental therapies designed to eliminate amyloid plaques fail to stop the progression of the disease. Brain cells will already be paralyzed before the plaques can fully form outside the neurons.
Research also suggests that controlling lysosomal functions may be a better therapeutic target. The latter can specifically focus on reversing lysosomal dysfunction and rebalancing acid levels in neurons. Another study from Langone University had identified the gene responsible for the problem of cellular waste disposal.
However, research so far has only focused on mice, and the mechanisms may be quite different in humans. Therefore, more studies are needed before this new hypothesis can be said to set aside the amyloid cascade.
Source: Nature Neuroscience
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