PLD3 gene and processing of APP

Cruchaga et al. 1 recently showed that:(1) variants in the phospholipase D3 (PLD3) gene confer increased risk for the development of Alzheimer’s disease (AD);(2) PLD3 expression is decreased in patients with sporadic Alzheimer’s disease; and (3) the expression of PLD3 inversely correlates with the expression of amyloid precursor protein (APP) and the production of amyloid-β peptides in vitro in cell lines. Altogether, the genetic and functional data led the authors to conclude that PLD3 loss-of-function confers an increased Alzheimer’s disease risk by affecting APP processing. We tested the relevance of PLD3 for APP processing in vivo in physiological conditions and in a relevant Alzheimer’s disease mouse model and found that PLD3 deficiency did not affect APP metabolism or amyloid plaque burden.