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.
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.
Authors: T Takahashi; A Fournier; F Nakamura; L H Wang; Y Murakami; R G Kalb; H Fujisawa; S M Strittmatter Journal: Cell Date: 1999-10-01 Impact factor: 41.582
Authors: L Tamagnone; S Artigiani; H Chen; Z He; G I Ming; H Song; A Chedotal; M L Winberg; C S Goodman; M Poo; M Tessier-Lavigne; P M Comoglio Journal: Cell Date: 1999-10-01 Impact factor: 41.582
Authors: Paul F Good; Daisy Alapat; Amy Hsu; Caryn Chu; Daniel Perl; Xiaping Wen; David E Burstein; D Stave Kohtz Journal: J Neurochem Date: 2004-11 Impact factor: 5.372
Authors: Matthew Brown; Tom Jacobs; Britta Eickholt; Giovanna Ferrari; Mabel Teo; Clinton Monfries; Robert Z Qi; Thomas Leung; Louis Lim; Christine Hall Journal: J Neurosci Date: 2004-10-13 Impact factor: 6.167
Authors: Adam R Cole; Axel Knebel; Nick A Morrice; Laura A Robertson; Andrew J Irving; Chris N Connolly; Calum Sutherland Journal: J Biol Chem Date: 2004-10-05 Impact factor: 5.157
Authors: Xiaoling Zhang; Congcong Zhu; Gary Beecham; Badri N Vardarajan; Yiyi Ma; Daniel Lancour; John J Farrell; Jaeyoon Chung; Richard Mayeux; Jonathan L Haines; Gerard D Schellenberg; Margaret A Pericak-Vance; Kathryn L Lunetta; Lindsay A Farrer Journal: Alzheimers Dement Date: 2019-01-03 Impact factor: 21.566
Authors: Gyungah R Jun; Jaeyoon Chung; Jesse Mez; Robert Barber; Gary W Beecham; David A Bennett; Joseph D Buxbaum; Goldie S Byrd; Minerva M Carrasquillo; Paul K Crane; Carlos Cruchaga; Philip De Jager; Nilufer Ertekin-Taner; Denis Evans; M Danielle Fallin; Tatiana M Foroud; Robert P Friedland; Alison M Goate; Neill R Graff-Radford; Hugh Hendrie; Kathleen S Hall; Kara L Hamilton-Nelson; Rivka Inzelberg; M Ilyas Kamboh; John S K Kauwe; Walter A Kukull; Brian W Kunkle; Ryozo Kuwano; Eric B Larson; Mark W Logue; Jennifer J Manly; Eden R Martin; Thomas J Montine; Shubhabrata Mukherjee; Adam Naj; Eric M Reiman; Christiane Reitz; Richard Sherva; Peter H St George-Hyslop; Timothy Thornton; Steven G Younkin; Badri N Vardarajan; Li-San Wang; Jens R Wendlund; Ashley R Winslow; Jonathan Haines; Richard Mayeux; Margaret A Pericak-Vance; Gerard Schellenberg; Kathryn L Lunetta; Lindsay A Farrer Journal: Alzheimers Dement Date: 2017-02-07 Impact factor: 16.655