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Basic Science and Pathogenesis.

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Phospholipase D3 (PLD3) variant impacts vascular function and inflammation, affecting endothelial and mural cells. This study reveals PLD3’s role in Alzheimer’s disease pathogenesis, particularly in vascular remodeling and amyloid precursor protein processing.

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Area of Science:

  • Neuroscience
  • Genetics
  • Vascular Biology

Background:

  • Genome-wide association studies (GWAS) link single-nucleotide polymorphisms (SNPs) to Late-Onset Alzheimer's Disease (LOAD).
  • A rare Phospholipase D3 (PLD3) variant (p.A442A) doubles LOAD risk and is implicated in Amyloid Precursor Protein (APP) processing.
  • Previous research suggested PLD3's role in mouse vascular function, but its specific actions in endothelial cells (ECs) and mural cells were unknown.

Purpose of the Study:

  • To investigate the impact of the PLD3 variant on vascular function and Alzheimer's disease (AD) pathogenesis.
  • To explore PLD3's role in endothelial cells (ECs) and mural cells using mouse models and human induced pluripotent stem cells (iPSCs).

Main Methods:

  • Utilized APP/PS1xPLD3 knockout (KO) mice and analyzed cortical RNA sequencing (RNA-seq) data.
  • Employed human iPSCs differentiated into ECs and mural cells, cultured in 2D and 3D vascular network models.
  • Assessed PLD3 variant and knockdown effects via RNA-seq, immunohistochemistry, cytokine release assays, and electric cell-substrate impedance sensing (ECIS) for EC barrier function.

Main Results:

  • In APP/PS1xPLD3 KO mice, vascular and inflammation pathways were downregulated, while protein degradation pathways were upregulated.
  • iPSC-derived ECs with the PLD3 variant or knockdown showed altered cell division and APP processing, impacting AD-GWAS genes.
  • PLD3 variant mural cells exhibited disrupted extracellular matrix remodeling (e.g., FN1, MMP25).
  • 3D vascular models with the PLD3 variant showed altered Interleukin-8 (IL-8) release, suggesting implications for vascular remodeling.

Conclusions:

  • PLD3 significantly influences vascular function and inflammation in mice, potentially contributing to Alzheimer's disease (AD) pathogenesis.
  • In human iPSC-derived vascular models, PLD3 regulates EC proliferation, APP processing, and mural cell matrix organization.
  • The PLD3 variant may induce vascular remodeling or instability, warranting further investigation into underlying mechanisms for potential therapeutic targeting.