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Alzheimer’s study tracks protein located inside cells

Apr. 15, 2021, 9:28 AM


by Paul Govern

New research from Vanderbilt University Medical Center, published recently in the journal PLOS Genetics, suggests an essential role for a somewhat obscure biomolecule and casts light on a potential drug target in Alzheimer’s disease.

Floating around inside animal cells are spherical sacs called lysosomes that contain digestive enzymes. Their activity analogous to the stomach, lysosomes break down large molecules and pass the fragments on to other parts of the cell for recycling. In mammals, depending on the cell type, there are 50 to 1,000 lysosomes per cell. Dysfunctional lysosome activity has been implicated in Alzheimer’s and other age-related diseases.

Matthew Schrag, MD, PhD

The new study, by neurologist Matthew Schrag, MD, PhD, and colleagues, is focused on phospholipase D3 (PLD3), a lysosomal protein described by the authors as poorly understood compared to other types of phospholipase, its function and its importance for lysosomal activity open to question.

PLD3’s day in the sun may have arrived with the new study.

“We found that people with PLD3 highly expressed in their prefrontal cortex appear protected from Alzheimer’s, that is, they’re less prone to cognitive decline and to the toxic buildup of extracellular plaques in their brains,” said Schrag, assistant professor of Neurology.

These findings are echoed in mice, the investigators found. In other findings from the study:

  • The team confirms that PLD3 does in fact localize to the lysosome, and, using various types of genetically modified mice and a human cell line, they establish that it’s a phospholipase D isoform after all, that is, it appears to have biological roles similar to those of its hardworking classmates PLD1 and PLD2, which are also implicated in Alzheimer’s disease.
  • Studying a rare genetic variant in PLD3 previously associated with Alzheimer’s, the investigators found that in mouse neurons the variant form of the protein significantly reduces lysosomal activity.
  • In a previous Alzheimer’s disease brain study, Schrag and colleagues had found that lysosome-like structures proliferate in misshapen parts of neurons found around toxic extracellular plaque. The new study confirms that these neuron sections are highly enriched with PLD3.

“The discovery of phospholipase D3 as a genetic risk factor for Alzheimer’s disease points to the critically important role of the lysosome in dementia,” Schrag said. “Our findings suggest an essential role for PLD3 in lysosomal function within axons, with important implications for cognition in the aged brain and in Alzheimer’s disease. Targeting experimental therapies to these lysosomes could lead us to new approaches to treat this disease.”

For their findings in humans, the investigators drew on data and specimens from the Religious Orders Study, the Rush Memory and Aging Project, and, for validation, the Accelerating Medicines Partnership AD project.

Other VUMC investigators on the study include lead author Alex Nackenoff, PhD, Timothy Hohman, PhD, Carolyn Akers, Nicole Weitzel, Alena Shostak and Angela Jefferson, PhD. They were joined by researchers from Rush University Medical Center, Yale University and the Jackson Laboratory.

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