New Alzheimer’s findings could lead to breakthrough in treatment
For decades, the fight against Alzheimer’s disease has targeted plaques on the outside of cells that are thought to represent a crucial connection between the disease and subsequent brain damage, but new research shows Alzheimer’s begins sooner and inside the cells.
The latest findings, published Thursday in the journal Nature Neuroscience, suggest neuronal damage from Alzheimer’s disease begins inside cells long before thread-like amyloid plaques – as described by the amyloid cascade hypothesis – fully form and clump together in the brain.
The study traced the initial dysfunction observed in mice bred to develop Alzheimer’s disease to small highly acidic sacs within cells, known as lysosomes. The acidic enzymes contained within lysosomes contribute to the routine breakdown, removal and recycling of metabolic waste from everyday cell reactions as well as from disease. Lysosomes are essential to breaking down and disposing of a cell’s own parts when a cell naturally dies, as well as causing the cell itself to self-destruct when a malfunction occurs.
Researchers at New York University’s Grossman School of Medicine and the Nathan Kline Institute for Psychiatric Research say the very earliest signs of Alzheimer’s are marked by a decrease of acidity inside lysosomes as cells become damaged by the disease.
“Our results for the first time sources [sic] neuronal damage observed in Alzheimer’s disease to problems inside brain cells’ lysosomes where amyloid beta first appears,” said the study’s lead investigator Ju-Hyun Lee, a research assistant professor in the NYU Langone Health Department of Psychiatry and research scientist at Nathan Kline.
“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,” Lee said in a statement.
As part of the study, researchers tracked decreasing acid activity inside intact mouse cell lysosomes as the cells became injured by Alzheimer’s.
Imaging tests developed at NYU Langone Health and Nathan Kline that tracked 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 – the amino acids that make up the amyloid plaques found inside the brains of Alzheimer’s patients.
“We started with looking at the human brain and documenting that the lysosomal system was both activated early in Alzheimer’s disease and then it starts to fail,” senior investigator Ralph Nixon, an NYU professor and director of the Center for Dementia Research at Nathan Kline, said Wednesday in a phone interview with Courthouse News.
Nixon said researchers then turned to the mouse models.
“The advantage more recently is having these mouse models to validate what we’ve seen in humans because we could genetically induce Alzheimer’s, causing genes and then follow the progression to the end stages of the disease,” he added. “So that has occupied a lot of our time in the last decade, and strategies to treat it have been the focus.”
Nixon said the use of mice is sometimes criticized for not being a perfect model, or because they don’t exhibit every single stage of Alzheimer’s. But, he said, “there isn’t a perfect model.”
He explained that because mice only live around 30 months, their short lifespan helps researchers learn a lot about development and progression of Alzheimer’s very quickly.
“We can start the model and go to 30 months within our own human lifetime,” he said during the phone call. “We can follow the early events and what becomes the latest events in 20-30 months. In some instances you can track the changes even faster.”
In the most heavily damaged neurons of Alzheimer’s sufferers, researchers have observed vacuoles clumped together in “flower-like” patterns and bulging out from the cells’ outer membranes to congregate around each cell’s center. Accumulations of amyloid beta form long strands inside the cell – one hallmark of Alzheimer’s disease.
“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,” Nixon said in a press release.
“Our research suggests that future treatments should focus on reversing the lysosomal dysfunction and rebalancing acid levels inside the brain’s neurons,” he said.
Nixon said researchers are already working on experimental therapies to treat the lysosomal problems observed in their findings.
Another study by the NYU Langone team that was published in April in Science Advances linked one source of cellular waste disposal problems to a gene called PSEN1 that has long been associated with Alzheimer’s disease but whose role in causing the illness through lysosomal dysfunction is only now becoming understood.
The research also indicated that the neuronal damage in a PSEN1 mouse model of the disease could be reversed by restoring proper acid levels in lysosomes.
The work is patented as a method of treating Alzheimer’s disease based on reversing lysosomal deacidification, the underlying cause of waste buildup. The terms and conditions of the patent are being managed in accordance with the policies of the health system, according to the press release.
“You can have impact on the brain through diet and exercise and through things of that sort that are beneficial for lowering the risk for Alzheimer’s disease, and that’s pretty well documented now,” Nixon said over the phone.
“That’s really what is I think is the way to look at it – that there are lifestyle modifications that you can make that will have a positive impact on the brain,” he said. “It’s just that if you have a stronger genetic risk for the disease, it’s not sufficient to modify it completely through lifestyle and diet and you need something that’s more powerful, and that’s what we’re looking for.”
According to the National Institute on Aging, more than 6 million Americans, most of them over 65, have dementia, a progressive loss of thinking, remembering, and reasoning, due to Alzheimer’s disease.