Alzheimer’s disease has long hampered our efforts to pinpoint its root causes. Now, a new study in mice shows that “poisonous flowers” littered with cell debris can be a source of a debilitating disease and a great danger sign that the waste disposal system inside the affected brain cells is failing.
A study led by New York University (NYU) neurobiologist Joo-hyun Lee disproves the long-held view that the accumulation of a protein called amyloid-beta among neurons is the first important step in Alzheimer’s disease. The most common type of dementia.
On the contrary, the breakdown of neurons suggests that amy plaques may form inside the cells and spread to the brain before they accumulate in the brain, a discovery that could provide new therapeutic possibilities.
“Our results suggest that the neuronal damage observed in Alzheimer’s disease for the first time leads to problems within the lysosomes of brain cells, where amyloid-beta first appears,” Lee said.
Although a study of a trio of human specimens and animals does not disprove current theories about what happens to the brain in Alzheimer’s disease, there is growing evidence that amyloid plaques do not actually develop the disease, but later. early trigger.
“Previously, the working hypothesis linked the damage observed in Alzheimer’s disease to the accumulation of amyloid outside the brain cells, rather than in front of and inside the neurons,” Lee said, referring to the amyloid cascade hypothesis in Alzheimer’s research. for three decades.
This hypothesis, which has never been generally accepted and is currently being tested, confirms that nodular groups of proteins called amyloids are the root cause of Alzheimer’s disease. The formation of these amyloid plaques between brain cells is thought to damage neurons, leading to memory loss and cognitive impairment.
But not everyone agrees, because the intracellular tentacles of another protein called a mountain are other major suspects of Alzheimer’s disease; and swollen, convex arms, usually curved neurons, are also part of the picture.
In this new study, researchers observed cellular dysfunction in mice bred to develop Alzheimer’s disease, down to the small sacs filled with brain cell lysosomes, cell debris, and processing enzymes.
Descriptive studies have shown that animal brain cells become diseased, that the lysosomes lose their normal acidity, grow, and then merge with amyloid protein fragments and vacuoles to carry other swollen waste.
Researchers have interpreted this as a sign that the neuron’s excretory system is not working and that the cells are under severe stress.
In the nucleus most severely damaged by cell death, these vacuoles turn into “large membranes” and form “flower-like” sockets around the cell. The researchers also identified amyloid plaques that were formed almost completely inside some damaged neurons.
Take a look at the picture below.
Called the “Poisonous Flower,” this unique specimen was found to be present in some brain cells of three people who died of Alzheimer’s disease.
However, more research is needed before this newly discovered feature can be said to be a contributing factor to Alzheimer’s disease.
Previous studies have shown that amyloid deposits in people with Alzheimer’s disease are very different from those found in animal models of the disease, and the latter is easier to clear from the brain.
So far, 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 basic understanding of how Alzheimer’s disease develops,” said neuroscientist Ralph Nixon, also of Langone, New York University.
“It also explains why many experimental therapies designed to destroy amyloid plaques have not been able to stop the disease from developing because the brain cells have become disabled before the plaques have fully formed outside the cell,” Nixon said.
Recently, the amyloid cascade hypothesis was rigorously re-examined 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, clears amyloid protein groups, and the decision has angered some Alzheimer’s researchers, who said it was too early to approve because the panel of judges did not answer the question of whether reducing amyloid levels actually slows cognitive decline.
Prior to that controversial decision, however, researchers questioned whether the accumulation of amyloid plaques could trigger Alzheimer’s disease or be a by-product that had nothing to do with it. This latest study adds fuel to the fire – or a small twig.
It is also in line with decades of research showing that amyloid groups grow from small fragments of ingested amyloid protein inside neurons and are expelled back into the cell after death.
Perhaps this new study, given that it is more common in mice, provides more detailed information on where and when amyloid plaques are formed, and shows the processes of waste disposal that cannot recycle cellular waste.
“Our research should focus on future treatment to restore lysosomal dysfunction and restore acid levels in brain neurons,” Nixon said.
New treatments for this tragic disease are certainly appealing. However, if we know anything about Alzheimer’s disease so far, researchers need to be careful when patients, their families, and even scientists lose hope in new therapies.
The study was published Nature Neuroscience.