Defining the Role of Phospholipase D3 in Alzheimer's Disease

Celeste Karch, PhD
Washington University School of Medicine (St. Louis, MO)
Year Awarded:
2015
Grant Duration:
July 1, 2015 to June 30, 2018
Disease:
Alzheimer's Disease
Award Amount:
$250,000
Grant Reference ID:
A2015411S
Award Type:
Standard
Award Region:
US Midwestern
Celeste Karch, PhD

Defining the Role of Phospholipase D3 in Alzheimer's Disease Pathogenesis

Summary

Alzheimer’s disease (AD) is the most common form of dementia but has no effective prevention or treatment. To develop novel therapeutic targets, it will be essential to understand the ways in which genetic variants associated with increased risk for AD may alter amyloid precursor protein (APP) metabolism and contribute to plaque pathology. We have identified genetic variants in phospholipase D3 (PLD3) that double the risk for late onset AD. The goal of this study is to use cell and mouse models to begin to define the molecular mechanisms by which PLD3 variants influence APP metabolism and contribute to AD pathology.

Details

Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β (Aβ) in the brain. The mechanism by which amyloid precursor protein (APP) is proteolyzed to generate Aβ is well understood; however, the role that other genes play in APP trafficking and Aβ production, clearance, and aggregation is poorly understood. APOE4 is a major risk factor for late onset AD that produces genotype-specific differences in Aβ clearance rates, illustrating the value of studying risk variants to understand AD pathogenesis. However, APOE4 only accounts for 50 percent of the genetic risk associated with late onset AD.

We have recently identified several coding variants in the phospholipase D3 (PLD3) gene that double the risk for developing late onset AD. Our preliminary data demonstrate that PLD3 is highly expressed in neurons and in regions of the brain that are most susceptible to AD pathology. Overexpression of PLD3 in cultured cells decreases extracellular Aβ levels while shRNA silencing of PLD3 increases extracellular Aβ levels. We also demonstrate that PLD3 has γ-secretase-dependent and – independent effects on APP metabolism. Together, these findings demonstrate that PLD3 plays a role in APP metabolism that contributes to AD pathogenesis; however, the mechanisms underlying these observations remain unclear.

The goal of this proposal is to begin to define the molecular mechanisms by which PLD3 influences AD risk. In this study we will use cell and mouse models to begin to define the mechanisms by which AD risk variants in PLD3 influence APP metabolism and contribute to AD pathology. Our group is using cell models to define the effects of PLD3 on APP metabolism and on proteins involved in generating the amyloid-beta (Aβ) peptides that accumulate in amyloid plaques in the brains of AD individuals. We are also using a mouse model of AD to examine the effects of PLD3 on Aβ metabolism and amyloid pathology in the brain. The results from these studies will increase our understanding of the precise mechanisms by which genetic risk variants in PLD3 regulates APP and Aβ metabolism, will provide novel insights into the underlying disease pathogenesis, and will allow for the identification of novel therapeutic targets for this devastating disease.

About the Researcher

Celeste Karch, PhD is an assistant professor of psychiatry at Washington University in St Louis. She received her doctoral degree from the University of Florida, where she worked with David Borchelt, PhD to study the mechanisms by which mutant SOD1 protein aggregates in cell and mouse models of amyotrophic lateral sclerosis. Dr. Karch joined Alison Goate, PhD, at Washington University as a postdoctoral fellow to examine the mechanisms by which cells release tau and how genetic variability associated with tauopathies influences tau release. Dr. Karch’s laboratory is focused on understanding the molecular mechanisms underlying tauopathies by studying genetic risk variants and disease-causing mutations in traditional immortalized cell, stem cell, and mouse models.  In addition to the BrightFocus award, Dr. Karch is funded by the National Institutes of Health.

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