Alzheimer’s The disease has long thwarted our best efforts to identify its underlying causes. Now, a new study in mice suggests that ‘poisonous flowers’ filled with cellular debris may be the source of a hallmark of miserable disease and a beautifully sinister sign of a failing waste disposal system in the body. inside damaged brain cells.
The study, led by New York University (NYU) Langone neuroscientist Ju-Hyun Lee, challenges the long-held idea that the buildup of a protein called beta-amyloid between neurons is a crucial first step in Alzheimer’s disease, the most common form of dementia.
Instead, it suggests that damage to neurons can take root inside cells long before amyloid plaques fully form and clump together in the brain, a finding that could offer new therapeutic possibilities.
“Our results attribute for the first time neuronal damage seen in Alzheimer’s disease to problems inside the lysosomes of brain cells where beta-amyloid first appears,” said Lee.
Although an animal study with a trio of human samples is not going to overturn existing theories on what happens to the brain in Alzheimer’s disease, the research is part of a growing body of evidence that suggests amyloid plaques are actually disease laggards rather than an early trigger.
“Previously, the working hypothesis attributed the damage seen in Alzheimer’s disease primarily to what happened after amyloid builds up outside of brain cells, not before and inside neurons.” , said Lee, taking aim at the amyloid cascade hypothesis that has gripped Alzheimer’s disease research for three decades.
This hypothesis, which has never been universally accepted and now on trial so to speak, posits that knotted clumps of a protein called amyloid are the 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 main suspects of Alzheimer’s disease; and swollen, bulging arms with usually spindly neurons are also part of the picture.
In this new study, the researchers traced the cellular dysfunction seen in mice bred to develop Alzheimer’s disease back to brain cell lysosomes, little sacs filled with acidic enzymes that break down and recycle waste within cells.
Imaging studies have shown that as animal brain cells become diseased, lysosomes lose their usual acidity, grow in size, and then fuse with other waste-bearing vacuoles already swollen with amyloid protein fragments and other debris.
The researchers took this as a sign that the neurons’ waste disposal systems were failing, putting the cells under extreme stress.
In the most damaged neurons destined for cell death, these vacuoles accumulated into “large membrane bubbles” forming “flower-like” rosettes around the cell nucleus. The researchers also spotted nearly fully formed amyloid plaques inside some damaged neurons.
Look at the picture below.
This unique pattern, dubbed a “poisonous flower”, was also present in some brain cells of three people who died of Alzheimer’s disease, the team found.
But much more research is needed before this new feature can be said to be a contributing factor to human Alzheimer’s disease.
Previous 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 these are also more easily eliminated from the brain.
For now, the researchers say their findings suggest that neurons containing these “poisonous flowers” may be the “primary source” of toxic amyloid plaques, at least in animal models of Alzheimer’s disease.
“This new evidence changes our fundamental understanding of the progression of Alzheimer’s disease,” said 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 paralyzed before the plaques form completely outside the cell. “, Nixon said. said.
Just recently, the amyloid cascade hypothesis has again come under intense scrutiny after the United States Federal Drug Administration approved a new treatment for Alzheimer’s disease in mid-2021 – the first in 18 years.
The drug, called aducanumab, clears clumps of amyloid protein and the decision sparked an outcry from some Alzheimer’s researchers who said approval was premature because the jury is still out whether reducing amyloid levels actually slows cognitive decline.
But even long before this controversial decision, the researchers wondered whether the accumulation of amyloid plaques triggers Alzheimer’s disease, causes its progression, or is an irrelevant by-product. This latest study just adds fuel – or a little twig – to that fire.
It also lines up with decade-old research suggesting that amyloid clusters grow inside neurons from small fragments of ingested amyloid protein, clumps that are then expelled into the intracellular space when the cell eventually dies.
Perhaps this new research – bearing in mind that it primarily involves mice – provides more granular details of where and when amyloid plaques form, pointing to faulty waste disposal processes that fail. to recycle cellular dirt.
“Our research suggests that future treatments should focus on reversing lysosomal dysfunction and rebalancing acid levels inside brain neurons,” Nixon said. said.
New therapeutic approaches are certainly welcome for this miserable disease. But if there’s anything we’ve learned about Alzheimer’s disease so far, it’s that researchers need to tread carefully when there’s such desperation among patients, their families, and even scientists themselves for new therapies.
The study was published in Natural neuroscience.
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