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 (FHS) (discovery) and NIA-LOAD (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 SNP (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 when stimulated by SEMA3A. The opposite effect was observed when transfected with shorter isoforms (TS2 and TS3). However, transfection of any isoform into HEK293 cells stably expressing 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.

Association study of the PLXNA4 gene with the risk of Alzheimer’s disease

“…According to the outcome of our case-control research, evidence shows the minor T allele play no effect the LOAD risk in the group of APOE ε4 carriers. This outcome is in different with Gyungah Jun's study in Japanese published in 2014 (22). The MAF of rs13232207 in healthy controls in our research was 0.229.…”

“…In addition, sample sizes in different investigation, population-specific differences as well as gene to gene or gene to environment interactions may also contribute towards this discrepancy in different ethnicity. PLXNA4 was first proposed to be associated with precise positioning of OPCs in developing cerebral cortex in 2012 (21), Jun's study then suggested that PLXNA4 do not influence APP processing or Aβ production but its isoform differentially affect Tau protein phosphorylation (22). Through the Tau phosphorylation, disrupted semaphorinplexin signaling is involved in AD pathogenesis, leading to neurofibrillary tangle formation and neuronal death (29).…”

“…The staining pattern of SEMA6 presenting in fibers and nerve terminals is also disrupted in brains of patients with AD (18-20). Okada's team reckoned that PLXNA4 was involved in the precise positioning of oligodendrocyte precursor cells (OPCs) in developing cerebral cortex (21), however, PLXNA4 is not involved in AD through the non-amyloidogenic or amyloidogenic processing of APP (22). These findings elucidate the modulating expression of the individual isoforms, which demonstrates that the genetic variation in PLXNA4 is associated with AD pathogenesis in brain tissue.…”

“…Research clarifies that rs75460865 and rs13232207 associate with LOAD risk in Caucasians and in Japanese respectively (22). The rs13232207 is located in the PLXNA4 region that encodes the cytoplasmic domain (22); however, there are no similar investigations in Chinese population by now. PLXNA4 gene variant and its frequency in various ethnic groups might be different.…”

An Overview of Genome-Wide Association Studies in Alzheimer’s Disease

“…A novel method of incorporating the entire family structure to reduce bias was used in a family-based GWAS, which generated strong evidence for a novel association of PLXNA4 with AD [62]. The first genome-wide epistasis study for AD was performed using GWAS data with a protocol for exhaustive epistasis screening, which revealed an AD-associated interacting SNP-pair of the KHDRBS2 and the CRYL1 genes [63].…”