Results could explain why drugs designed to remove amyloid deposits have failed to stop disease.
According to the National Institute on Aging, Alzheimer’s disease is the most common cause of dementia in older adults and the 7th leading cause of death in the United States. It is a debilitating progressive illness that slowly destroys cognitive function and memory.
The amyloid cascade hypothesis is a leading theory for how Alzheimer’s disease forms. Now, new research findings point in a new direction.
A breakdown in how brain cells rid themselves of waste precedes the buildup of debris-filled plaques known to occur in Alzheimer’s disease, a new study in mice shows.
The field argued for decades that such plaques, containing the protein amyloid beta, built up outside of cells as a crucial first step toward the brain damage observed in Alzheimer’s disease. Led by researchers at NYU Grossman School of Medicine and the Nathan Kline Institute, the new study challenges this idea, known as the amyloid cascade hypothesis.
The latest study findings argue instead that neuronal damage characteristic of Alzheimer’s disease takes root inside cells and well before these thread-like amyloid plaques fully form and clump together in the brain.
High-resolution image, as seen by fluorescent microscopy, shows flower-like formations of autophagic vacuoles in neurons of Alzheimer’s disease mouse.
Credit: Courtesy of Springer-Nature Publishing
Published on June 2, 2022, as the cover article in the journal Nature Neuroscience, the study traced the root dysfunction observed in mice bred to develop Alzheimer’s disease to the brain cells’ lysosomes. These are small sacs inside every cell, filled with acidic enzymes involved in the routine breakdown, removal, and recycling of metabolic waste from everyday cell reactions, as well as from disease. Lysosomes are also key, researchers note, to breaking down and disposing of a cell’s own parts when the cell naturally dies.
As part of the study, researchers tracked decreasing acid activity inside intact mouse cell lysosomes as the cells became injured in the disease. Imaging tests developed at NYU Langone Health and Nathan Kline (to track cellular waste removal) showed that certain brain cell lysosomes became enlarged as they fused with so-called autophagic vacuoles filled with waste that had failed to be broken down. These autophagic vacuoles also contained earlier forms of amyloid beta.
Credit: Courtesy of Springer-Nature Publishing
In neurons most heavily damaged and destined for early death as a result, the vacuoles pooled together in “flower-like” patterns, bulging out from the cells’ outer membranes and massing around each cell’s center, or nucleus. Accumulations of amyloid beta formed filaments inside the cell, another hallmark of Alzheimer’s disease. Indeed, researchers observed almost-fully formed plaques inside some damaged neurons.
“Our results for the first time sources neuronal damage observed in Alzheimer’s disease to problems inside brain cells’ lysosomes where amyloid beta first appears,” says study lead investigator Ju-Hyun Lee, PhD.
“Previously, the working hypothesis mostly attributed the damage observed in Alzheimer’s disease to what came after amyloid buildup outside of brain cells, not before and from within neurons,” says Lee, a research assistant professor in the Department of Psychiatry and NYU Langone Health and research scientist at Nathan Kline.
In neurons most heavily damaged and destined for early death as a result, the vacuoles pooled together in “flower-like” patterns, bulging out from the cells’ outer membranes and massing around each cell’s center, or nucleus. Accumulations of amyloid beta formed filaments inside the cell, another hallmark of Alzheimer’s disease. Indeed, researchers observed almost-fully formed plaques inside some damaged neurons.
“Our results for the first time sources neuronal damage observed in Alzheimer’s disease to problems inside brain cells’ lysosomes where amyloid beta first appears,” says study lead investigator Ju-Hyun Lee, PhD.
“Previously, the working hypothesis mostly attributed the damage observed in Alzheimer’s disease to what came after amyloid buildup outside of brain cells, not before and from within neurons,” says Lee, a research assistant professor in the Department of Psychiatry and NYU Langone Health and research scientist at Nathan Kline.
Credit: Courtesy of Springer-Nature Publishing
“This new evidence changes our fundamental understanding of how Alzheimer’s disease progresses; it also explains why so 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,” says study senior investigator Ralph Nixon, MD, PhD.
“Our research suggests that future treatments should focus on reversing the lysosomal dysfunction and rebalancing acid levels inside the brain’s neurons,” says Nixon, a professor in the Department of Psychiatry and the Department of Cell Biology at NYU Langone, as well as director of the Center for Dementia Research at Nathan Kline.
Researchers say they are already working on experimental therapies to treat the lysosomal problems observed in their studies.
“This new evidence changes our fundamental understanding of how Alzheimer’s disease progresses; it also explains why so 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,” says study senior investigator Ralph Nixon, MD, PhD.
“Our research suggests that future treatments should focus on reversing the lysosomal dysfunction and rebalancing acid levels inside the brain’s neurons,” says Nixon, a professor in the Department of Psychiatry and the Department of Cell Biology at NYU Langone, as well as director of the Center for Dementia Research at Nathan Kline.
Researchers say they are already working on experimental therapies to treat the lysosomal problems observed in their studies.
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