PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer's disease.

Alex G Nackenoff,Nicole C Weitzel,Sarah M Neuner,Timothy J Hohman,David A Bennett,Carolyn S Akers,Matthew S Schrag,Julie A Schneider,Shawn M Ferguson,Angela L Jefferson,Bret Mobley,Alena Shostak,Catherine C Kaczorowski,J Nicholas Cochran

doi:10.1371/journal.pgen.1009406

Abstract

Phospholipase D3 (PLD3) is a protein of unclear function that structurally resembles other members of the phospholipase D superfamily. A coding variant in this gene confers increased risk for the development of Alzheimer’s disease (AD), although the magnitude of this effect has been controversial. Because of the potential significance of this obscure protein, we undertook a study to observe its distribution in normal human brain and AD-affected brain, determine whether PLD3 is relevant to memory and cognition in sporadic AD, and to evaluate its molecular function. In human neuropathological samples, PLD3 was primarily found within neurons and colocalized with lysosome markers (LAMP2, progranulin, and cathepsins D and B). This colocalization was also present in AD brain with prominent enrichment on lysosomal accumulations within dystrophic neurites surrounding β-amyloid plaques. This pattern of protein distribution was conserved in mouse brain in wild type and the 5xFAD mouse model of cerebral β-amyloidosis. We discovered PLD3 has phospholipase D activity in lysosomes. A coding variant in PLD3 reported to confer AD risk significantly reduced enzymatic activity compared to wild-type PLD3. PLD3 mRNA levels in the human pre-frontal cortex inversely correlated with β-amyloid pathology severity and rate of cognitive decline in 531 participants enrolled in the Religious Orders Study and Rush Memory and Aging Project. PLD3 levels across genetically diverse BXD mouse strains and strains crossed with 5xFAD mice correlated strongly with learning and memory performance in a fear conditioning task. In summary, this study identified a new functional mammalian phospholipase D isoform which is lysosomal and closely associated with both β-amyloid pathology and cognition.

Highlights

Alzheimer’s disease (AD) is the most common form of dementia and an increasing societal and economic burden
We discovered that Phospholipase D3 (PLD3) expression levels correlate β-amyloid plaque density and the rate of cognitive decline in the longitudinal Religious Orders Study and Rush Memory and Aging Project
These discoveries establish that PLD3 is an important AD risk gene and implicate PLD3 in the neurobiology of lysosomal dysfunction in AD

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia and an increasing societal and economic burden. Multiple gene variants were recently discovered in the Phospholipase D3 (PLD3) gene which conferred increased risk for late onset AD [1]. Phospholipase D enzymes (PLDs) form a superfamily that are present in viruses, bacteria, and plants all the way up to mammalian cells. PLD3 was identified as a PLD based upon homology as it contains two HKD motifs, but two prior studies informally reported that PLD3 lacks PLD activity, the data and methodology were not presented [6,7]. The PLD3 gene variants associated with increased late onset AD risk were initially linked to β-amyloid precursor protein (APP) processing [1] but this could only be replicated in overexpression conditions [8]. Because the variant is rare (~1% of affected patients)[1], the relevance of PLD3 to AD processes at a population level is yet unknown

Objectives

Methods

Results

Discussion

Conclusion