Cellular ‘garbage disposal’ units fingered in Alzheimer’s development

Lysosomes play an important role in cells: They break down old material so the body can dispose of it. Now, scientists at Yale University are zeroing in on lysosomes in the brain, and they believe they’ve discovered how these “garbage disposal” units may contribute to the buildup of the amyloid plaques characteristic of Alzheimer’s disease.

The Yale researchers discovered defects in the process by which lysosomes travel within neurons. And when this transport goes wrong, lysosomes build up in swollen axons that surround amyloid-beta, the protein that’s associated with brain plaques. The team published the findings in The Journal of Cell Biology.

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When lysosomes travel from the ends of axons into the center of neuronal cells, they mature and develop the ability to degrade old cell components. But sometimes they get stuck in swollen axons and fail to mature. The Yale scientists weren’t sure how this defect contributed to the buildup of amyloid plaque, so they designed an experiment in which they interfered with the transport of lysosomes in mouse neurons.

They discovered that when neurons are deprived of a protein called JIP3, they fail to properly transport lysosomes from the axons, according to a statement. Swollen axons also accumulate amyloid precursor protein (APP) and two enzymes that cause APP to generate amyloid-beta: BACE1 and presenilin 2.

When the team removed a copy of the gene that makes JIP3 from mouse models of Alzheimer’s, the animals produced more amyloid-beta, and they formed larger plaques surrounded by an increased number of swollen axons.

"Collectively, our results indicate that the axonal accumulations of lysosomes at amyloid plaques are not innocent bystanders but rather are important contributors to APP processing and amyloid plaque growth," said co-author Shawn Ferguson of the Yale School of Medicine in the statement.

The so-called “amyloid hypothesis” in Alzheimer’s remains controversial. Many neurological researchers believe amyloid plaques are central players in the disease. But efforts to target those plaques with drugs have been disappointing so far. One of the most high-profile anti-amyloid drugs was solanezumab, Eli Lilly’s experimental Alzheimer’s drug, which the company abandoned in 2016 after years of failed trials.

But researchers are still investigating new ways of preventing amyloid from building up in the brain. In June, for example, a University of Cambridge team described computer-generated antibodies they developed that prevent amyloid-beta from clumping together and forming plaques.

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The Yale scientists believe that as they learn more about how deficiencies in lysosome transport contribute to amyloid plaques, they may be able to identify strategies for modulating proteins in the brain to repair the process. Their research might also aid efforts underway to examine how genetics and other risk factors—including traumatic brain injuries—contribute to Alzheimer’s.