Neural ‘Poisonous Flowers’ Could Be the Source of Alzheimer’s Disease, Study Says

alzheimer’s disease has long thwarted our efforts to identify the underlying causes. Now, a new study in mice suggests that “poisonous flowers” bulging with cell debris may be the cause of a hallmark of the wretched disease and a wonderfully sinister sign of a failing waste-processing system in damaged brain cells.

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

Instead, it suggests that damage to neurons can take root in cells long before amyloid plaques fully form and clump together in the brain, a finding that could open up new therapeutic possibilities.

“Our results for the first time cause neuronal damage seen in Alzheimer’s disease to problems in the lysosomes of brain cells, where amyloid beta first appears,” say Lee.

Although one animal study with three human samples did not support existing theories about what happens to the brain? in Alzheimer’s disease, the research is part of a growing body of evidence that suggests that amyloid plaques are actually latecomers to the disease rather than an early trigger.

“In the past, the working hypothesis attributed the damage seen in Alzheimer’s disease mainly to what came after amyloid buildup outside brain cells, not before and from neurons,” say Lee, targeting the amyloid cascade hypothesis that gripped Alzheimer’s research for three decades

That hypothesis, which has never been universally accepted and now on trial so to speak, states that knotted clumps of a protein called amyloid are the main 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 intracellular tangles of another protein called tau are the other prime suspects in Alzheimer’s disease; and the swollen, bulging arms of mostly spindly neurons are also part of the picture.

In this new study, researchers traced the cellular dysfunction seen in mice bred to develop Alzheimer’s disease into brain cell lysosomes, tiny sacs filled with acidic enzymes that break down and recycle waste in cells.

Imaging studies showed that as the animals’ brain cells became diseased, lysosomes lost their usual acidity, expanded and then fused with other waste-carrying vacuoles that already swelled with fragments of amyloid proteins and other debris.

The researchers saw this as a sign that the neurons’ waste-processing systems were failing, putting the cells under extreme stress.

In the most severely damaged neurons destined for cell death, these vacuoles gathered into “large membrane bubbles” and formed “flower-like” rosettes around the cell nucleus. Researchers also spied nearly fully formed amyloid plaques in some damaged neurons.

Have a look at the image below.

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

This unique pattern, called a “poisonous flower,” was also present in some brain cells in three people who had died of Alzheimer’s disease, the team found.

But much more research is needed before we can say that this new trait is a contributing factor to Alzheimer’s disease in humans.

Past research suggests that amyloid deposits in people with Alzheimer’s disease are: very different from those found in animal models of the disease and that the latter are also more easily cleared from the brain.

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

“This new evidence changes our fundamental understanding of how Alzheimer’s progresses,” say neurobiologist Ralph Nixon, also of NYU Langone.

“It also explains why so many experimental therapies designed to remove amyloid plaques have failed to stop disease progression because brain cells are already crippled before the plaques form completely outside the cell,” Nixon say

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

The drug, called aducanumab, removes clumps of amyloid protein, and the decision sparked outrage from some Alzheimer’s researchers who said the approval was premature because the jury isn’t here yet on whether reducing amyloid levels actually slows cognitive decline.

But even long before that controversial decision, researchers wondered whether the accumulation of amyloid plaques causes Alzheimer’s disease, stimulates its progression, or is an irrelevant by-product. This latest study just adds fuel — or a small twig — to that fire.

It also fits with decade-old research suggesting that: amyloid clumps grow in neurons of small fragments of ingested amyloid protein, clumps that are then expelled back into the intracellular space when the cell eventually dies.

Perhaps this new research — bearing in mind that it’s mostly in mice — will provide more detailed details about where and when amyloid plaques form, pointing to faulty waste-handling processes failing to recycle cellular gunk.

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

New therapeutic approaches are certainly welcome for this miserable disease. But if there’s one thing we’ve learned about Alzheimer’s so far, it’s that researchers should be cautious when there’s such desperation among patients, their families, and even scientists themselves for new therapies.

The study is published in Nature Neuroscience

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