In another victory for whole-genome technology, geneticists have identified rare variants of phospholipase D3 (PLD3) that double a person’s risk for late-onset Alzheimer’s disease (LOAD). Lead author Carlos Cruchaga of Washington University School of Medicine, St. Louis, reported the gist of the findings at the Alzheimer’s Association International Conference in July (Aug 2013 conference story). A December 11 Nature paper now details the full analysis, including functional and expression data suggesting that PLD3 curbs processing of amyloid precursor protein (APP) and that brain levels of this lipase fall in AD.

Whereas 15 percent of individuals carry the top LOAD allele, apolipoprotein E4 (ApoE4), which triples disease risk, less than 1 percent of the population harbors the PLD3 mutations identified in the current study. To hunt down such rare variants, researchers led by senior author Alison Goate of Washington University sequenced the coded portions of the genome—the exome—of 29 afflicted and 11 healthy members of 14 LOAD families. If a variant segregated with disease in one family, the researchers looked to see if the association held in additional families. One variant passed muster. The V232M PLD3 mutation showed up in all afflicted members but not in healthy members of two independent families. The researchers confirmed that this variant conferred elevated LOAD risk, independent of ApoE genotype, in seven datasets containing more than 11,000 cases and controls.

Sequencing the PLD3 exome in another 4,600 people in two populations of European and African descent, the team found a second PLD3 variant, A442A, that associated with LOAD risk. “This consistent evidence of association with AD risk, at the single-nucleotide polymorphism (SNP) and gene level in two different populations, strongly supports PLD3 as an AD risk gene,” the authors write.

The discovery comes about a year after two research groups rooted out mutations in the microglial receptor TREM2, which increase LOAD risk 1.5- to threefold (Nov 2012 news story; Oct 2013 news story). One of these groups found an even rarer APP mutation that protects against the disease (Jul 2012 news story). “The harvest of new genes identified by whole-genome technologies continues,” said John Hardy, University College London, who led one of the TREM2 studies and was one of more than 80 co-authors on the PLD3 paper. Both genes seem tied to Aβ—TREM2 in phagocytic responses to the peptide, PLD3 in its production, Hardy suggested.

In cognitively healthy elderly, PLD3 is mainly expressed in the brain, particularly in the frontal, temporal, and occipital cortices, and the hippocampus. Its expression drops in AD, the authors report. Scientists understand little about PLD3’s function, but have implicated its family members in APP processing and AD. PLD1 may promote trafficking of APP-loaded vesicles through the trans-Golgi network and bind presenilin 1 to block Ab production (Feb 2006 news story; Liu et al., 2009). There are hints that PLD2 may be critical for Ab toxicity, as AD mice lacking this lipase resist synaptic and memory deficits (Oliveira et al., 2010).

In their current study, the authors found that PLD3 stymies APP processing in vitro. When Cruchaga and colleagues transfected human PLD3 lipase into N2A mouse neuroblastoma cells that stably express human APP, the cells secreted half as much Aβ; Aβ production doubled when the researchers used short-hairpin RNAs to knock down endogenous PLD3 expression. The scientists are creating mouse models with the newly discovered PLD3 mutations to get a better handle on how the gene contributes to AD pathogenesis, Cruchaga told Alzforum.—Esther Landhuis

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References

News Citations

  1. Scientists Hunting Rare Alzheimer’s Mutations Eye Phospholipase D3
  2. Enter the New Alzheimer’s Gene: TREM2 Variant Triples Risk
  3. Fall Flurry of Letters Kicks Up Dust Around TREM2
  4. Protective APP Mutation Found—Supports Amyloid Hypothesis
  5. AβPP Processing—Limping Along on Lipases

Paper Citations

  1. . Intracellular trafficking of presenilin 1 is regulated by beta-amyloid precursor protein and phospholipase D1. J Biol Chem. 2009 May 1;284(18):12145-52. PubMed.
  2. . Phospholipase d2 ablation ameliorates Alzheimer's disease-linked synaptic dysfunction and cognitive deficits. J Neurosci. 2010 Dec 8;30(49):16419-28. PubMed.

External Citations

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Further Reading

Papers

  1. . Phospholipase d2 ablation ameliorates Alzheimer's disease-linked synaptic dysfunction and cognitive deficits. J Neurosci. 2010 Dec 8;30(49):16419-28. PubMed.

Primary Papers

  1. . Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer’s disease. Nature (11 December 2013)