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Title | PLXNA4 is associated with Alzheimer disease and modulates tau phosphorylation. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Jun G, Asai H, Zeldich E, Drapeau E, Chen CD, Chung J, Park J-H, Kim S, Haroutunian V, Foroud T, Kuwano R, Haines JL, Pericak-Vance MA, Schellenberg GD, Lunetta KL, Kim J-W, Buxbaum JD, Mayeux R, Ikezu T, Abraham CR, Farrer LA |
Journal | Ann Neurol |
Volume | 76 |
Issue | 3 |
Pagination | 379-92 |
Date Published | 2014 Sep |
ISSN | 1531-8249 |
Keywords | Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Protein Precursor, Animals, Cohort Studies, Female, Frontal Lobe, Genetic Predisposition to Disease, Genome-Wide Association Study, HEK293 Cells, Hippocampus, Humans, Male, Pedigree, Phosphorylation, Polymorphism, Single Nucleotide, Protein Isoforms, Rats, Receptors, Cell Surface, tau Proteins |
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).INTERPRETATION: Our results indicate that PLXNA4 has a role in AD pathogenesis through isoform-specific effects on tau phosphorylation. |
DOI | 10.1002/ana.24219 |
Alternate Journal | Ann. Neurol. |
PubMed ID | 25043464 |
PubMed Central ID | PMC4830273 |
Grant List | PG30-AG13846 / AG / NIA NIH HHS / United States U24 AG021886 / AG / NIA NIH HHS / United States U01 AG032984 / AG / NIA NIH HHS / United States P30 AG013846 / AG / NIA NIH HHS / United States P01 AG000001 / AG / NIA NIH HHS / United States R01-AG025259 / AG / NIA NIH HHS / United States U24-AG021886 / AG / NIA NIH HHS / United States R37 AG015473 / AG / NIA NIH HHS / United States U24 AG026395 / AG / NIA NIH HHS / United States U24-AG26395 / AG / NIA NIH HHS / United States R01 AG041797 / AG / NIA NIH HHS / United States R01-AG041797 / AG / NIA NIH HHS / United States P50 AG005138 / AG / NIA NIH HHS / United States N01HC25195 / HL / NHLBI NIH HHS / United States R01 AG025259 / AG / NIA NIH HHS / United States R01-AG0001 / AG / NIA NIH HHS / United States P50-AG005138 / AG / NIA NIH HHS / United States |