Study Says Neurotoxin 'Toxic Flowers' Could Be the Source of Alzheimer's Plaque

Study Says Neurotoxin ‘Toxic Flowers’ Could Be the Source of Alzheimer’s Plaque

Alzheimer’s disease has long frustrated our best efforts to identify its underlying causes. Now, a new study in mice suggests that “poisonous flowers” swollen with cellular debris could be the root source of one of the hallmarks of this wretched disease and a pretty sinister sign of the failure of the waste disposal system within damaged brain cells.

The study, led by neuroscientist Joo Hyun Lee of New York University (NYU) Langone, challenges the old idea that the buildup of a protein called amyloid beta between neurons is a critical first step in Alzheimer’s disease, the most common form of dementia.

Instead, she suggests, damage to neurons may take root within cells well before amyloid plaques fully form and clump together in the brain, a finding that could offer new therapeutic possibilities.

“Our results for the first time attribute the neurological damage observed in Alzheimer’s disease to problems within the corpuscles of brain cells where amyloid-beta first appears,” Lee says.

Although one animal study with three human samples won’t override existing theories about what happens to the brain in Alzheimer’s disease, the research is part of a growing body of evidence suggesting that amyloid plaques are in fact those who are late in the disease and not Early trigger.

“Previously, the working hypothesis attributed the damage observed in Alzheimer’s disease to what occurred after amyloid buildup outside brain cells, rather than before and within neurons,” Lee says, targeting the amyloid cascade hypothesis that has dominated Alzheimer’s research for three decades.

This hypothesis, which has not been universally accepted and is now being tested so to speak, posits that complex clumps of a protein called amyloid are the root cause of Alzheimer’s disease. The buildup of these amyloid plaques between brain cells is thought to damage neurons, leading to memory loss and cognitive decline.

But not everyone agrees because the intracellular tangles of another protein called tau are the other prime suspects in Alzheimer’s disease. The bulging and bulging arms of the deep neurons are also part of the picture.

In this new study, researchers traced the cellular imbalance observed in mice bred to develop Alzheimer’s disease to lysosomes in brain cells, which are small sacs filled with acidic enzymes that break down and recycle waste in cells.

Imaging studies have shown that when the animals’ brain cells become diseased, the lysosomes lose their usual acidity, swell, and then fuse with other waste-carrying vacuoles that are already swollen with fragments of amyloid proteins and other debris.

The researchers took this as a sign that the litter disposal systems in neurons had failed, putting the cells under severe stress.

In the most severely damaged neurons destined for cell death, these vacuoles assemble into “large membranous bubbles” forming “flower-like” rosettes around the cell nucleus. The researchers also spied on nearly fully formed amyloid plaques inside some of the damaged neurons.

Take a look at the image below.

Flower-like formations in Alzheimer’s disease mouse neurons. (Li et al., Nat. Neurosci, 2022)

The team found that this unique pattern, dubbed “poisonous flower,” was also present in some brain cells of three people who died of Alzheimer’s disease.

But more research is needed before we can say that this newly discovered feature is a contributing factor to human Alzheimer’s disease.

Previous research suggests that amyloid deposits in people with Alzheimer’s are very different from those in animal models of the disease and that the latter is also easier to remove from the brain.

For now, the researchers say their findings suggest that neurons containing these “toxic flowers” could be the “main source” of toxic amyloid plaques, at least in animal models of Alzheimer’s disease.

“This new evidence changes our basic understanding of how Alzheimer’s disease progresses,” says neuroscientist Ralph Nixon, of NYU Langone.

“It also explains why many experimental therapies designed to remove amyloid plaques fail to stop disease progression because brain cells are already paralyzed before the plaques can fully form outside the cell,” Nixon says.

Recently, the amyloid cascade hypothesis came under intense scrutiny again after the US Federal Drug Administration approved a new treatment for Alzheimer’s disease in mid-2021 — the first in 18 years.

The drug, called aducanumab, removes clumps of the amyloid protein and the decision sparked outrage from some Alzheimer’s researchers who said approval was premature because the jury was still out on whether reducing amyloid levels actually slowed cognitive decline.

But even long before this controversial decision, researchers were wondering whether the buildup of amyloid plaques leads to Alzheimer’s disease, leads to its development, or is an unrelated byproduct. This latest study is adding fuel — or a little twig — to that fire.

It also fits with a decade of research suggesting that clumps of amyloid grow inside neurons from tiny fragments of the engulfed amyloid protein, clumps that are expelled back into the intracellular space when the cell eventually dies.

Perhaps this new research—considering that it’s mostly in mice—provides more subtle details about where and when amyloid plaques form, pointing to faulty waste disposal processes that fail to recycle cellular sticky material.

“Our research suggests that future treatments should focus on reversing lysosomal dysfunction and rebalancing acid levels within neurons in the brain,” Nixon says.

Certainly, new therapeutic approaches are welcome for this miserable disease. But if there’s anything we’ve learned so far about Alzheimer’s disease, it’s that researchers must tread with caution when there is such desperation among patients, their families, and even scientists themselves for new treatments.

The study was published in Natural Neuroscience.

2022-06-05 06:00:53

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