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2017 Alzheimer's Association Research Grant (AARG)

A role for PLD3 in the autophagy-lysosome pathway and Aß clearance

How can a “waste disposal” protein in the brain affect the development of beta-amyloid plaques in Alzheimer’s disease?

Celeste Karch, Ph.D.
Washington University in St.Louis
St. Louis, MO - United States


A major hallmark of Alzheimer’s disease is the clumping of beta-amyloid, a protein fragment, into sticky plaques within the brain. This clumping may occur, in part, because the brain loses its ability to clear beta-amyloid molecules effectively. However, scientists remain uncertain exactly how harmful beta-amyloid is cleared from the brain, and how this clearance mechanism might be damaged in Alzheimer’s.

Celeste Karch, Ph.D., and colleagues have been examining amyloid clearance in (1) autopsied brain tissue from people with Alzheimer’s disease and (2) mice engineered to develop Alzheimer’s-like symptoms. They found that a protein called phospholipase D3 (PLD3) played a major role in this process. PLD3 is found in lysosomes, the cellular compartments that help degrade and dispose of waste in cells through a series of chemical reactions that occur in the autophagy-lysosome pathway. The researchers also observed that nerve cells from human Alzheimer’s brain tissue had significantly low levels of PLD3 activity. In addition, they found that by genetically reducing PLD3 activity in an Alzheimer’s-like mouse model, they could increase the levels of beta-amyloid production in those mice. Taken together, these findings suggest that PLD3 may help prevent the development of amyloid plaques and the onset of Alzheimer’s.

Research Plan

For their grant, the investigators will determine PLD3’s role in the autophagy-lysosome pathway and in beta-amyloid clearance. First, using Alzheimer’s-like mice with low PLD3 levels, they will assess how the lack of PLD3 alters the way beta-amyloid is transported and degraded in the body. Second, using human neurons in a dish derived from stem cells, they will assess how PLD3 affects the development and function of lysosomes needed to degrade beta-amyloid.


Taken together, the results of these efforts will improve our understanding of how amyloid plaques develop in Alzheimer’s disease. They could also identify PLD3 as a novel target for future Alzheimer’s therapies.

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