Neurexin 3 transmembrane and soluble isoform expression and splicing haplotype are associated with neuron inflammasome and Alzheimer's disease

Akitoyo Hishimoto, Olga Pletnikova, Doyle Lu Lang, Juan C Troncoso, Josephine M. Egan, Qing Rong Liu

Research output: Contribution to journalArticle

Abstract

Background: Synaptic damage precedes neuron death in Alzheimer's disease (AD). Neurexins, NRXN1, NRXN2, and NRXN3, are presynaptic adhesion molecules that specify neuron synapses and regulate neurotransmitter release. Neurexins and postsynaptic neuroligins interact with amyloid beta oligomer (AβO) deposits in damaged synapses. NRXN3 gene variants have been associated with autism, addiction, and schizophrenia, however, not fully investigated in Alzheimer's disease. In the present study, we investigated an AD association of a 3′-splicing allele of rs8019381 that produces altered expression of transmembrane or soluble NRXN3 isoforms. Methods: We carried out RT-PCR (reverse transcription polymerase chain reaction), PCR-RFLP (PCR and restriction fragment length polymorphism), Sanger sequencing, and in situ hybridization (ISH) assays for NRXN3 neuron expression and genotyping. Genetic associations were analyzed by χ 2 tests, and ISH signals were analyzed by FISH v1.0 module of Indica Labs HALO software. Results: We previously identified a functional haplotype in the 3′ region of neurexin 3 (NRXN3) gene that alters the expression ratios between NRXN3 transmembrane and soluble isoforms. In this study, we found that expression and ratio of transmembrane and soluble NRXN3 isoforms were reduced in AD postmortem brains and inversely correlated with inflammasome component NLRP3 in AD brain regions. The splicing haplotype related to the transmembrane and soluble NRXN3 expression was associated with AD samples with P = 6.3 × 10 -5 (odds ratio = 2.48) and interacted with APOE genotypes. Conclusions: We found that the SNP rs8019381 of NRXN3 that is located adjacent to splicing site #5 (SS#5) interacts with the APOE ϵ4 haplotype and alters NRXN3 transmembrane or soluble isoform expression in AD postmortem cortex. Dysregulation of presynaptic NRXN3 expression and splicing might increase neuron inflammation in AD brain.

Original languageEnglish (US)
Article number28
JournalAlzheimer's Research and Therapy
Volume11
Issue number1
DOIs
StatePublished - Mar 21 2019

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Inflammasomes
Haplotypes
Alzheimer Disease
Protein Isoforms
Neurons
Synapses
In Situ Hybridization
Brain
Polymerase Chain Reaction
Autistic Disorder
Amyloid
Restriction Fragment Length Polymorphisms
Reverse Transcription
Single Nucleotide Polymorphism
Neurotransmitter Agents
Schizophrenia
Software
Alleles
Odds Ratio
Genotype

Keywords

  • Alternative splicing
  • Alzheimer's disease
  • Apolipoprotein E
  • Endocannabinoids
  • Neurexins

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cognitive Neuroscience

Cite this

Neurexin 3 transmembrane and soluble isoform expression and splicing haplotype are associated with neuron inflammasome and Alzheimer's disease. / Hishimoto, Akitoyo; Pletnikova, Olga; Lang, Doyle Lu; Troncoso, Juan C; Egan, Josephine M.; Liu, Qing Rong.

In: Alzheimer's Research and Therapy, Vol. 11, No. 1, 28, 21.03.2019.

Research output: Contribution to journalArticle

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abstract = "Background: Synaptic damage precedes neuron death in Alzheimer's disease (AD). Neurexins, NRXN1, NRXN2, and NRXN3, are presynaptic adhesion molecules that specify neuron synapses and regulate neurotransmitter release. Neurexins and postsynaptic neuroligins interact with amyloid beta oligomer (AβO) deposits in damaged synapses. NRXN3 gene variants have been associated with autism, addiction, and schizophrenia, however, not fully investigated in Alzheimer's disease. In the present study, we investigated an AD association of a 3′-splicing allele of rs8019381 that produces altered expression of transmembrane or soluble NRXN3 isoforms. Methods: We carried out RT-PCR (reverse transcription polymerase chain reaction), PCR-RFLP (PCR and restriction fragment length polymorphism), Sanger sequencing, and in situ hybridization (ISH) assays for NRXN3 neuron expression and genotyping. Genetic associations were analyzed by χ 2 tests, and ISH signals were analyzed by FISH v1.0 module of Indica Labs HALO software. Results: We previously identified a functional haplotype in the 3′ region of neurexin 3 (NRXN3) gene that alters the expression ratios between NRXN3 transmembrane and soluble isoforms. In this study, we found that expression and ratio of transmembrane and soluble NRXN3 isoforms were reduced in AD postmortem brains and inversely correlated with inflammasome component NLRP3 in AD brain regions. The splicing haplotype related to the transmembrane and soluble NRXN3 expression was associated with AD samples with P = 6.3 × 10 -5 (odds ratio = 2.48) and interacted with APOE genotypes. Conclusions: We found that the SNP rs8019381 of NRXN3 that is located adjacent to splicing site #5 (SS#5) interacts with the APOE ϵ4 haplotype and alters NRXN3 transmembrane or soluble isoform expression in AD postmortem cortex. Dysregulation of presynaptic NRXN3 expression and splicing might increase neuron inflammation in AD brain.",
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AU - Pletnikova, Olga

AU - Lang, Doyle Lu

AU - Troncoso, Juan C

AU - Egan, Josephine M.

AU - Liu, Qing Rong

PY - 2019/3/21

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AB - Background: Synaptic damage precedes neuron death in Alzheimer's disease (AD). Neurexins, NRXN1, NRXN2, and NRXN3, are presynaptic adhesion molecules that specify neuron synapses and regulate neurotransmitter release. Neurexins and postsynaptic neuroligins interact with amyloid beta oligomer (AβO) deposits in damaged synapses. NRXN3 gene variants have been associated with autism, addiction, and schizophrenia, however, not fully investigated in Alzheimer's disease. In the present study, we investigated an AD association of a 3′-splicing allele of rs8019381 that produces altered expression of transmembrane or soluble NRXN3 isoforms. Methods: We carried out RT-PCR (reverse transcription polymerase chain reaction), PCR-RFLP (PCR and restriction fragment length polymorphism), Sanger sequencing, and in situ hybridization (ISH) assays for NRXN3 neuron expression and genotyping. Genetic associations were analyzed by χ 2 tests, and ISH signals were analyzed by FISH v1.0 module of Indica Labs HALO software. Results: We previously identified a functional haplotype in the 3′ region of neurexin 3 (NRXN3) gene that alters the expression ratios between NRXN3 transmembrane and soluble isoforms. In this study, we found that expression and ratio of transmembrane and soluble NRXN3 isoforms were reduced in AD postmortem brains and inversely correlated with inflammasome component NLRP3 in AD brain regions. The splicing haplotype related to the transmembrane and soluble NRXN3 expression was associated with AD samples with P = 6.3 × 10 -5 (odds ratio = 2.48) and interacted with APOE genotypes. Conclusions: We found that the SNP rs8019381 of NRXN3 that is located adjacent to splicing site #5 (SS#5) interacts with the APOE ϵ4 haplotype and alters NRXN3 transmembrane or soluble isoform expression in AD postmortem cortex. Dysregulation of presynaptic NRXN3 expression and splicing might increase neuron inflammation in AD brain.

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KW - Endocannabinoids

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