title: PLXNA4 is associated with Alzheimer disease and modulates tau phosphorylation.
abstract: OBJECTIVE
  Much of the genetic basis for Alzheimer disease (AD) is unexplained. We sought to identify novel AD loci using a unique family-based approach that can detect robust associations with infrequent variants (minor allele frequency < 0.10).
  
  
  METHODS
  We conducted a genome-wide association study in the Framingham Heart Study (discovery) and NIA-LOAD (National Institute on Aging-Late-Onset Alzheimer Disease) Study (replication) family-based cohorts using an approach that accounts for family structure and calculates a risk score for AD as the outcome. Links between the most promising gene candidate and AD pathogenesis were explored in silico as well as experimentally in cell-based models and in human brain.
  
  
  RESULTS
  Genome-wide significant association was identified with a PLXNA4 single nucleotide polymorphism (rs277470) located in a region encoding the semaphorin-3A (SEMA3A) binding domain (meta-analysis p value [meta-P] = 4.1 × 10(-8) ). A test for association with the entire region was also significant (meta-P = 3.2 × 10(-4) ). Transfection of SH-SY5Y cells or primary rat neurons with full-length PLXNA4 (TS1) increased tau phosphorylation with stimulated by SEMA3A. The opposite effect was observed when cells were transfected with shorter isoforms (TS2 and TS3). However, transfection of any isoform into HEK293 cells stably expressing amyloid β (Aβ) precursor protein (APP) did not result in differential effects on APP processing or Aβ production. Late stage AD cases (n = 9) compared to controls (n = 5) had 1.9-fold increased expression of TS1 in cortical brain tissue (p = 1.6 × 10(-4) ). Expression of TS1 was significantly correlated with the Clinical Dementia Rating score (ρ = 0.75, p = 2.2 × 10(-4) ), plaque density (ρ = 0.56, p = 0.01), and Braak stage (ρ = 0.54, p = 0.02).
  
  
  CONCLUSIONS
  Our results indicate that PLXNA4 has a role in AD pathogenesis through isoform-specific effects on tau phosphorylation.
authors.affiliation: Departments of Medicine, Boston University School of Medicine, Boston, MA; Ophthalmology, Boston University School of Medicine, Boston, MA; Department of Biostatistics, Boston University School of Public Health, Boston, MA.
authors.forename: Gyungah
authors.initials: G
authors.lastname: Jun
authors.forename: Hirohide
authors.initials: H
authors.lastname: Asai
authors.forename: Ella
authors.initials: E
authors.lastname: Zeldich
authors.forename: Elodie
authors.initials: E
authors.lastname: Drapeau
authors.forename: CiDi
authors.initials: C
authors.lastname: Chen
authors.forename: Jaeyoon
authors.initials: J
authors.lastname: Chung
authors.forename: Jong-Ho
authors.initials: JH
authors.lastname: Park
authors.forename: Sehwa
authors.initials: S
authors.lastname: Kim
authors.forename: Vahram
authors.initials: V
authors.lastname: Haroutunian
authors.forename: Tatiana
authors.initials: T
authors.lastname: Foroud
authors.forename: Ryozo
authors.initials: R
authors.lastname: Kuwano
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Lunetta
authors.forename: Jong-Won
authors.initials: JW
authors.lastname: Kim
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.forename: Richard
authors.initials: R
authors.lastname: Mayeux
authors.forename: Tsuneya
authors.initials: T
authors.lastname: Ikezu
authors.forename: Carmela R
authors.initials: CR
authors.lastname: Abraham
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D015331:Cohort Studies; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008297:Male; D010375:Pedigree; D010766:Phosphorylation / Q000235:genetics / Q000502:physiology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; C524474:Plxna4 protein, human; D020033:Protein Isoforms; D011956:Receptors, Cell Surface; D016875:tau Proteins