2020 Alzheimer's Association Research Fellowship (AARF)

The Lysosomal Exonuclease PLD3 as a Late-Onset Alzheimer Risk Factor

Could variations in a “waste disposal” process cause other proteins to clump inside nerve cells in Alzheimer’s?
 

Zoë Van Acker, Ph.D.
Katholieke Universiteit
Leuven, Belgium

Background

The beta-amyloid and tau proteins accumulate and form plaques and tangles, respectively, the two main hallmark brain changes observed in Alzheimer’s. This may occur, in part, when nerve cells lose their ability to clear waste effectively. Phospholipase D3 (PLD3) is a protein found in lysosomes, compartments inside the cell that helps degrade and dispose of waste. Specifically, PLD3 is an “exonuclease” – a kind of protein that degrades pieces of DNA that are no longer needed. Studies show people with variations in the gene providing instructions for PLD3 may be at a higher risk of developing late-onset Alzheimer’s.
 

Research Plan

Dr. Zoë Van Acker and colleagues will determine how abnormal functioning of PLD3 can lead to protein clumping inside nerve cells.  First, the researchers will examine nerve cells in laboratory dishes using specialized microscopes to identify the kinds of DNA that PLD3 most commonly attaches to inside lysosomes. Dr. Van Acker’s team will also employ a special technique to collect lysosomes from the nerve cells and study their contents. The researchers will compare lysosomes between healthy nerve cells and nerve cells genetically engineered to have genetic variations in PLD3. Dr. Van Acker’s team will then look for ways in which the genetic variations in PLD3 variations might impact waste disposal systems inside the nerve cells.
 
Finally, the researchers will use a special type of stem cell from human adult tissue, called iPSCs (induced Pluripotent Stem Cells) from cognitively unimpaired individuals and those with Alzheimer’s.  iPSCs can be programmed to grow into any type of cell in the human body. The researchers will use iPSCs to create nerve cells in laboratory dishes and will confirm their findings in these nerve cells genetically engineered Alzheimer’s-like mice.
 

Impact

If successful, this study could reveal ways in which waste disposal systems inside nerve cells may go awry and how it may be associated with protein clumping in the brain, in Alzheimer’s. Dr. Van Acker’s work may also help identify PLD3 as a novel target for potential Alzheimer’s therapies.
 

This project was made possible by the Dale Schenk Alzheimer's Association Research Roundtable Award.