Alzheimer’s disease has long thwarted our best efforts to determine its underlying causes. Now, a new study in mice suggests that “poisonous flowers” bulging with cellular debris may be at the root of a hallmark of the wretched disease and a beautifully sinister sign of a failing waste disposal system in damaged brain cells.
The study, led by New York University (NYU) Langone neuroscientist Ju-Hyun Lee, challenges the longstanding notion that the building up of a protein called amyloid beta between neurons is a crucial first step in the common form of Alzheimer’s disease 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 avenues.
“Our results, for the first time, lead neuronal damage seen in Alzheimer’s disease to problems in the lysosomes of brain cells, where beta-amyloid first appears,” says Lee.
Although an animal study using a trio of human samples won’t overturn 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 tend to be latecomers of the disease as an early trigger.
“Previously, the working hypothesis attributed the damage seen in Alzheimer’s disease mainly to what came after amyloid accumulation outside of brain cells, not before and inside neurons,” says Lee, targeting the amyloid cascade hypothesis, which Alzheimer’s research has been recording for three decades.
This hypothesis, which was never widely accepted and is now on trial, so to speak, suggests that knotted clumps of a protein called amyloid are the main cause of Alzheimer’s disease. The accumulation of these amyloid plaques between brain cells is believed 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 normally scrawny neurons are also part of the image.
In this new study, the researchers attributed the cellular dysfunction seen in mice bred to develop Alzheimer’s disease to the brain cells’ lysosomes, small sacs filled with acidic enzymes that break waste into cells dismantle and recycle.
Imaging studies showed that as the animals’ brain cells became diseased, the lysosomes lost their usual acidity, enlarged, and then merged with other waste-carrying vacuoles that were already swollen with fragments of amyloid proteins and other debris.
The researchers took this as a sign that the neurons’ waste disposal systems were failing, putting extreme strain on the cells.
In the most damaged neurons destined for cell death, these vacuoles pooled into “large membrane vesicles” and formed “flower-like” rosettes around the nucleus. The researchers also discovered almost fully formed amyloid plaques in some damaged neurons.
Check out the image below.
This unique pattern, dubbed the “poisonous flower,” was also present in some brain cells of three people who died from Alzheimer’s disease, the team found.
But far more research is needed before we can say that this newly discovered trait is a contributing factor to Alzheimer’s disease in humans.
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 the latter are also more easily cleared from the brain.
The researchers say their findings initially suggest that neurons containing these “poisonous flowers” may be the “major 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 disease progresses,” says neurobiologist Ralph Nixon, also of NYU Langone.
“It also explains why so many experimental therapies designed to remove amyloid plaques have failed to halt disease progression because the brain cells are already crippled before the plaques have completely formed outside the cell,” says Nixon.
The amyloid cascade hypothesis was recently put under renewed scrutiny 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 an outcry from some Alzheimer’s researchers, who said the approval was premature because it’s yet to be decided whether reducing amyloid levels actually slows cognitive decline.
But long before this controversial decision, researchers questioned whether the formation of amyloid plaques triggers Alzheimer’s disease, fuels its progression, or is an irrelevant by-product. This latest study just adds fuel — or a tiny branch — to that fire.
It also fits with decades of research suggesting that clumps of amyloid in neurons grow from small fragments of ingested amyloid protein, clumps that are then ejected back into the intracellular space when the cell eventually dies.
Perhaps, considering it’s mostly mice, this new research will provide more specific details about where and when amyloid plaques form, and point to faulty waste-disposal processes that don’t recycle cellular debris.
“Our research suggests that future treatments should focus on reversing lysosomal dysfunction and rebalancing the acid levels in the brain’s neurons,” says Nixon.
New therapeutic approaches to this wretched disease are welcome. But if we’ve learned anything about Alzheimer’s so far, it’s that researchers should tread carefully when patients, their families, and even scientists themselves are so desperate for new therapies.
The study was published in nature neuroscience.