ArticleAnnals of neurology2014
PLXNA4 is associated with Alzheimer disease and modulates tau phosphorylation.
Article in Annals of neurology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 67 citations in OpenAlex.
- Interactive effects of telomere length and genetic variants on Alzheimer disease risk across multiple ancestral populations.Alzheimer's research & therapy · 2026Article
- Neuronal guidance signaling in neurodegenerative diseases: Key regulators that function at neuron-glia and neuroimmune interfaces.Neural regeneration research · 2026Article
- Mapping Alzheimer's disease heterogeneity through exploratory unsupervised learning.Frontiers in aging neuroscience · 2026Article
- Systematic analysis of cellular cross-talk reveals a role for SEMA6D-TREM2 regulating microglial function in Alzheimer's disease.Science translational medicine · 2025Article
- Common Variants in PLXNA4 and Correlation to Neuroimaging Phenotypes in Healthy, Mild Cognitive Impairment, and Alzheimer's Disease Cohorts.Molecular neurobiology · 2025Article
- Navigating the blurred boundary: Neuropathologic changes versus clinical symptoms in Alzheimer's disease, and its consequences for research in genetics.Journal of Alzheimer's disease : JAD · 2025Review
- A comparative study of structural variant calling in WGS from Alzheimer's disease families.Life science alliance · 2024Article
- Population structure and selective signature of Kirghiz sheep by Illumina Ovine SNP50 BeadChip.PeerJ · 2024Article
- Alzheimer's Disease: An Updated Overview of Its Genetics.International journal of molecular sciences · 2023Review
- Interactions between genes involved in physiological dysregulation and axon guidance: role in Alzheimer's disease.Frontiers in genetics · 2023Article
- PlexinA1-deficient mice exhibit decreased cell density and augmented oxidative stress in parvalbumin-expressing interneurons in the medial prefrontal cortex.IBRO neuroscience reports · 2022Article
- Association of mitochondrial variants and haplogroups identified by whole exome sequencing with Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2022Article
- Review
- Advances in Genetics and Epigenetic Alterations in Alzheimer's Disease: A Notion for Therapeutic Treatment.Genes · 2021Review
- Enrichment of Phosphorylated Tau (Thr181) and Functionally Interacting Molecules in Chronic Traumatic Encephalopathy Brain-derived Extracellular Vesicles.Aging and disease · 2021Article
- An artificial neural network approach integrating plasma proteomics and genetic data identifies PLXNA4 as a new susceptibility locus for pulmonary embolism.Scientific reports · 2021Article
- Roles and Mechanisms of Axon-Guidance Molecules in Alzheimer's Disease.Molecular neurobiology · 2021Review
- Systematic analysis to identify transcriptome-wide dysregulation of Alzheimer's disease in genes and isoforms.Human genetics · 2021Article
- Semaphorins in Adult Nervous System Plasticity and Disease.Frontiers in synaptic neuroscience · 2021Review
- PlexinA1 deficiency in BALB/cAJ mice leads to excessive self-grooming and reduced prepulse inhibition.IBRO reports · 2020Article
Corrections and comments
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Authors and funding
21 authors at 12 institutions in 3 countries.
Funding
Abstract
objectiveMuch 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).
methodsWe 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.
resultsGenome-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).
interpretationOur results indicate that PLXNA4 has a role in AD pathogenesis through isoform-specific effects on tau phosphorylation.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.