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Cited by 59Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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

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Nackenoff, Alex G., Hohman, Timothy J., Neuner, Sarah M., Akers, Carolyn S., Weitzel, Nicole C., Shostak, Alena, Ferguson, Shawn M., Mobley, Bret +5 more·2021·PLOS Genetics
DOI 10.1371/journal.pgen.1009406PMC PMC8031396

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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.

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Crossref · 10.1371/journal.pgen.1009406

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  • Pld3 has been shown to be downregulated in the hippocampus of AD patient brains.

    “Expression of another gene, Pld3 (Phospholipase D3), that has been shown to be downregulated in the hippocampus of AD patient brains, 21 was also decreased in 5XFAD/MR1 KO compared to 5XFAD mice.”

    From The MR1/MAIT cell axis enhances dystrophic neurite development in Alzheimer's disease (2025) · cites this paper as [21]

    The Results report lower PLD3 levels in human AD cases than in cognitively normal participants, but the Methods identify the sampled human tissue as dorsolateral prefrontal cortex. The reported reduction in hippocampal PLD3 mRNA is in AD-BXD mice, not human patients. Although the Fig. 3 caption calls the human measurements hippocampal, that conflicts with the Methods and the surrounding Results, so the claimed human hippocampal finding is not established by this copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • PLD3 levels are negatively correlated with Aβ and cognitive function.

    “PLD3 levels have been reported to be negatively correlated with Aβ and cognitive function, 21 , 34”

    From The MR1/MAIT cell axis enhances dystrophic neurite development in Alzheimer's disease (2025) · cites this paper as [21]

    The Results section reports that higher prefrontal cortex PLD3 expression was associated with lower β-amyloid plaque burden. But it also associates higher PLD3 expression with slower cognitive decline, not poorer cognitive function; the claimed negative correlation with cognitive function reverses that relationship. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • PLD3 is thought to be a risk gene in late-onset AD, and found alongside other lysosomal markers, such as LAMP2, in human tissue.

    “It is also thought to be a risk gene in late‐onset AD, and found alongside other lysosomal markers, such as LAMP2, in human tissue; 21”

    From The MR1/MAIT cell axis enhances dystrophic neurite development in Alzheimer's disease (2025) · cites this paper as [21]

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Authors
Nackenoff, A. G., Hohman, T. J., Neuner, S. M., Akers, C. S., Weitzel, N. C., Shostak, A., Ferguson, S. M., Mobley, B., Bennett, D. A., Schneider, J. A., Jefferson, A. L., Kaczorowski, C. C., & Schrag, M. S.
Affiliations
  • Vanderbilt University Medical Center (US)
  • Jackson Laboratory (US)
  • Yale University (US)
  • Rush University Medical Center (US)
Corresponding author
Schrag, Matthew S.
ORCID
Venue
PLOS Genetics
Publisher
Public Library of Science (PLoS)
Published
2021-04-08
Volume
17
Issue
4
Pages
e1009406
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1009406
PMC
PMC8031396
OpenAlex
W3146592250
Cited by
59
References
6
Citations by year
2026: 10 · 2025: 12 · 2024: 16 · 2023: 12 · 2022: 6 · 2021: 3
FWCI
5.80
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Vanderbilt Faculty Research Scholars
  • National Institute of Neurological Disorders and Stroke (1R03NS111486)
  • National Institute on Aging; American Federation of Aging Research (K76 AG060001, T32-AG058524, K01 AG049164, R01 AG059716, R21 AG059941)
  • Vanderbilt Memory and Alzheimer's Center
  • National Institute on Aging, Resilience-AD program (R01AG057914)
  • BrightFocus Foundation (A2016397S)
  • National Institute on Aging (R01AG054180, F31AG050357)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
PLD3, phospholipase D, Alzheimer's disease, amyloid plaques, lysosomes, dystrophic neurites, cognitive decline, memory, 5xFAD mice, genetic risk variants, LAMP2, progranulin, cathepsins, fear conditioning, prefrontal cortex
MeSH terms
Alzheimer Disease, Animals, Autopsy, Disease Models, Animal, Exodeoxyribonucleases, HeLa Cells, Humans, Lysosomes, Neurons, Phospholipase D, Genetic Predisposition to Disease, Mice, Plaque, Amyloid, Cognitive Dysfunction

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