Premium
PLXNA 4 is associated with A lzheimer disease and modulates tau phosphorylation
Author(s) -
Jun Gyungah,
Asai Hirohide,
Zeldich Ella,
Drapeau Elodie,
Chen CiDi,
Chung Jaeyoon,
Park JongHo,
Kim Sehwa,
Haroutunian Vahram,
Foroud Tatiana,
Kuwano Ryozo,
Haines Jonathan L.,
PericakVance Margaret A.,
Schellenberg Gerard D.,
Lunetta Kathryn L.,
Kim JongWon,
Buxbaum Joseph D.,
Mayeux Richard,
Ikezu Tsuneya,
Abraham Carmela R.,
Farrer Lindsay A.
Publication year - 2014
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.24219
Subject(s) - gene isoform , transfection , minor allele frequency , genome wide association study , hek 293 cells , biology , phosphorylation , in silico , single nucleotide polymorphism , allele , genetics , gene , microbiology and biotechnology , allele frequency , genotype
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). Interpretation Our results indicate that PLXNA4 has a role in AD pathogenesis through isoform‐specific effects on tau phosphorylation. Ann Neurol 2014;76:379–392