title: PLD3 is accumulated on neuritic plaques in Alzheimer's disease brains.
abstract: BACKGROUND
  Recently, a whole-exome sequencing (WES) study showed that a rare variant rs145999145 composed of p.Val232Met located in exon 7 of the phospholipase D3 (PLD3) gene confers a doubled risk for late-onset Alzheimer's disease (AD). Knockdown of PLD3 elevates the levels of extracellular amyloid-beta (Aβ), suggesting that PLD3 acts as a negative regulator of Aβ precursor protein (APP) processing. However, the precise cellular location and distribution of PLD3 in AD brains remain largely unknown.
  
  
  METHODS
  By quantitative RT-PCR (qPCR), western blot, immunohistochemistry, and bioinformatics analysis, we studied PLD3 expression patterns and levels in a series of AD and control brains, including amyotrophic lateral sclerosis, Parkinson's disease, multiple system atrophy, and non-neurological cases.
  
  
  RESULTS
  The levels of PLD3 mRNA and protein expression were reduced modestly in AD brains, compared with those in non-AD brains. In all brains, PLD3 was expressed constitutively in cortical neurons, hippocampal pyramidal and granular neurons but not in glial cells. Notably, PLD3 immunoreactivity was accumulated on neuritic plaques in AD brains. We identified the human granulin (GRN) gene encoding progranulin (PRGN) as one of most significant genes coexpressed with PLD3 by bioinformatics database search. PLD3 was actually coexpressed and interacted with PGRN both in cultured cells in vitro and in AD brains in vivo.
  
  
  CONCLUSIONS
  We identified an intense accumulation of PLD3 on neuritic plaques coexpressed with PGRN in AD brains, suggesting that PLD3 plays a key role in the pathological processes of AD.
authors.affiliation: Department of Bioinformatics and Molecular Neuropathology, Meiji, Pharmaceutical University, 2-522-1 Noshio, Kiyose 204-8588, Tokyo, Japan.
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Satoh
authors.affiliation: Department of Bioinformatics and Molecular Neuropathology, Meiji, Pharmaceutical University, 2-522-1 Noshio, Kiyose 204-8588, Tokyo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kino
authors.affiliation: Department of Bioinformatics and Molecular Neuropathology, Meiji, Pharmaceutical University, 2-522-1 Noshio, Kiyose 204-8588, Tokyo, Japan.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Department of Bioinformatics and Molecular Neuropathology, Meiji, Pharmaceutical University, 2-522-1 Noshio, Kiyose 204-8588, Tokyo, Japan.
authors.forename: Natsuki
authors.initials: N
authors.lastname: Kawana
authors.affiliation: Department of Pathology and Laboratory Medicine, Kohnodai Hospital, NCGM, 1-7-1 Kohnodai, Ichikawa 272-8516, Chiba, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Ishida
authors.affiliation: Department of Laboratory Medicine, National Center Hospital, NCNP, 4-1-1 Ogawahigashi, Kodaira 187-8502, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Department of Psychiatry, Komoro Kogen Hospital, Kou 4598, Komoro 384-8540, Nagano, Japan.
authors.forename: Kunimasa
authors.initials: K
authors.lastname: Arima