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PLXNA4 is associated with Alzheimer disease and modulates tau phosphorylation.
Ann Neurol. 2014 Sep; 76(3):379-92.AN

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.

Authors+Show Affiliations

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.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25043464

Citation

Jun, Gyungah, et al. "PLXNA4 Is Associated With Alzheimer Disease and Modulates Tau Phosphorylation." Annals of Neurology, vol. 76, no. 3, 2014, pp. 379-92.
Jun G, Asai H, Zeldich E, et al. PLXNA4 is associated with Alzheimer disease and modulates tau phosphorylation. Ann Neurol. 2014;76(3):379-92.
Jun, G., Asai, H., Zeldich, E., Drapeau, E., Chen, C., Chung, J., Park, J. H., Kim, S., Haroutunian, V., Foroud, T., Kuwano, R., Haines, J. L., Pericak-Vance, M. A., Schellenberg, G. D., Lunetta, K. L., Kim, J. W., Buxbaum, J. D., Mayeux, R., Ikezu, T., ... Farrer, L. A. (2014). PLXNA4 is associated with Alzheimer disease and modulates tau phosphorylation. Annals of Neurology, 76(3), 379-92. https://doi.org/10.1002/ana.24219
Jun G, et al. PLXNA4 Is Associated With Alzheimer Disease and Modulates Tau Phosphorylation. Ann Neurol. 2014;76(3):379-92. PubMed PMID: 25043464.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PLXNA4 is associated with Alzheimer disease and modulates tau phosphorylation. AU - Jun,Gyungah, AU - Asai,Hirohide, AU - Zeldich,Ella, AU - Drapeau,Elodie, AU - Chen,CiDi, AU - Chung,Jaeyoon, AU - Park,Jong-Ho, AU - Kim,Sehwa, AU - Haroutunian,Vahram, AU - Foroud,Tatiana, AU - Kuwano,Ryozo, AU - Haines,Jonathan L, AU - Pericak-Vance,Margaret A, AU - Schellenberg,Gerard D, AU - Lunetta,Kathryn L, AU - Kim,Jong-Won, AU - Buxbaum,Joseph D, AU - Mayeux,Richard, AU - Ikezu,Tsuneya, AU - Abraham,Carmela R, AU - Farrer,Lindsay A, Y1 - 2014/07/29/ PY - 2014/04/13/received PY - 2014/07/02/revised PY - 2014/07/02/accepted PY - 2014/7/22/entrez PY - 2014/7/22/pubmed PY - 2014/12/15/medline SP - 379 EP - 92 JF - Annals of neurology JO - Ann Neurol VL - 76 IS - 3 N2 - 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. SN - 1531-8249 UR - https://www.unboundmedicine.com/medline/citation/25043464/PLXNA4_is_Associated_with_Alzheimer_Disease_and_Modulates_Tau_Phosphorylation DB - PRIME DP - Unbound Medicine ER -