Alzheimer's disease has prevented us from figuring out its underlying causes. A new study in mice suggests that poisonous flowers bulging with cellular debris could be the root cause of one of the hallmark diseases and a beautifully sinister sign of a failing waste disposal system inside damaged brain cells.
The study, led by Ju-Hyun Lee of New York University Langone, challenges the idea that the build-up of aamyloid-beta between neurons is a crucial first step in Alzheimer's disease.
It suggests that damage to neurons may take root inside cells before amyloid plaques form and clump together in the brain, a finding which could provide new therapeutic possibilities.
According to Lee, the results for the first time show damage to brain cells caused by amyloid-beta.
The research is part of a growing body of evidence that suggests amyloid plaques are actually latecomers to the disease rather than an early cause.
Lee takes aim at the amyloid cascade hypothesis that has gripped Alzheimer's research for three decades.
The hypothesis that clumps of amyloid are the root cause of Alzheimer's disease is currently on trial and has never been accepted by the general public. Alzheimer's disease is thought to be caused by the build up of amyloid plaques between brain cells.
The swollen, bulging arms of usually spindly neurons are also part of the picture.
The brain cells' lysosomes, small sacs filled with acidic enzymes that break down and recycle waste in cells were the focus of the new study.
As the animals' brain cells became sick, lysosomes lost their acidity, became enlarged, and then fused with other waste-carrying vacuoles already swelling with fragments of amyloid.
The researchers thought this was a sign that the garbage disposal systems were malfunctioning.
In the most damaged cells, the vacuoles accumulate into large blebs and form flowers around the nucleus. Some damaged neurons were spied by researchers.
You can take a look at the picture.
Flower-like formations in neurons of Alzheimer's disease mouse. (Lee et al., Nat. Neurosci., 2022)
Some brain cells in three people who had died from Alzheimer's disease had a pattern called a poisonous flower.
We don't know if this feature is a contributing factor in human Alzheimer's disease.
The amyloid deposits found in people with Alzheimer's disease are different from those found in animal models of the disease, according to past research.
At least in animal models of Alzheimer's disease, the researchers think that the poisonous flowers could be the main source of toxic amyloid plaques.
"This new evidence changes our understanding of how Alzheimer's disease progresses," says Nixon.
It explains why many experimental therapies designed to remove amyloid plaques have failed to stop disease progression because the brain cells are already crippled before the plaques fully form outside the cell.
The amyloid cascade hypothesis was once again under scrutiny after the US Federal Drug Administration approved a new therapy for Alzheimer's disease.
Some Alzheimer's researchers said the approval of the drug was premature because the jury is still out on whether it slows cognitive decline.
Researchers were questioning if the build-up of amyloid plaques causes Alzheimer's disease or if it is an irrelevant by-product. Fuel is added to the fire by this latest study.
It's similar to a decade-old research that suggests that amyloid clumps grow inside neurons from small fragments of ingested amyloid, which then get expelled back into intracellular space when the cell dies.
This new research might provide more information about where and when amyloid plaques form, pointing to faulty waste disposal processes that don't recycle cellular gunk.
Nixon says that their research suggests that future treatments should focus on reversing the lysosomal function.
There are new approaches to treatment for this terrible disease. If there's anything we've learned so far about Alzheimer's, it's that researchers should be careful when trying to find new treatments.
The study was published in a scientific journal.
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