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

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.

Phospholipase D3 contributes to Alzheimer’s disease risk via disruption of Aβ clearance and microglia response to amyloid plaques

“…Founders were established and backcrossed to C57Bl/6;C3B6 prior to breeding with APP/PS1 mice (Supplemental Figure 3C). Consistent with prior reports, Pld3 KO mice were viable and did not exhibit gross defects [9, 31]. Pld3 -deficient APP/PS1 mice exhibited a 35% increase in steady-state ISF Aβ at four months of age (Figure 3G-3I).…”

“…Neurons from Pld3 KO mice exhibit lysosomes with increased density and size [31]. PLD3 is enriched in lysosomes surrounding amyloid plaques in human AD brains and mouse models of amyloid accumulation [9]. Thus, Pld3 may regulate ISF Aβ through lysosome-mediated clearance mechanisms in neurons or other glial cells.…”

“…PLD3 is a non-classical member of the phospholipase D (PLD) family of enzymes, with no known function [5–7]. PLD3 is expressed in pyramidal neurons within the brain, and in AD brains, PLD3 co-localizes with amyloid plaques [8, 9]. Common variants in PLD3 are associated with CSF Aβ levels, an AD biomarker [10].…”

Challenge accepted: uncovering the role of rare genetic variants in Alzheimer’s disease

“…PLD3 expression levels were also found to correlate with βamyloid plaque density and the rate of cognitive decline in humans. Similarly, PLD3 expression levels correlated with memory and learning in a genetically diverse mouse model [83]. However, since the initial association of PLD3 with AD, independent studies with sufficient power to detect similar genetic effects have all failed to replicate the association [84][85][86][87][88].…”

Autophagy and Mitophagy-Related Pathways at the Crossroads of Genetic Pathways Involved in Familial Sarcoidosis and Host-Pathogen Interactions Induced by Coronaviruses

“…Closely associated to ER, phospholipase D3 (encoded by PLD3) is expressed into intraluminal vesicles of multivesicular endosomes and colocalized with amyloid precursor (APP). Mutations of PLD3 are considered to be a genetic factor involved in late onset Alzheimer's disease associated with an increased processing of APP to Aβ [90]. Interestingly, the accumulation of amyloid peptides is a hallmark of sarcoid granulomas [91].…”