TY - JOUR
T1 - Neurexin 3 transmembrane and soluble isoform expression and splicing haplotype are associated with neuron inflammasome and Alzheimer's disease
AU - Hishimoto, Akitoyo
AU - Pletnikova, Olga
AU - Lang, Doyle Lu
AU - Troncoso, Juan C.
AU - Egan, Josephine M.
AU - Liu, Qing Rong
PY - 2019/3/21
Y1 - 2019/3/21
N2 - 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.
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.
KW - Alternative splicing
KW - Alzheimer's disease
KW - Apolipoprotein E
KW - Endocannabinoids
KW - Neurexins
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U2 - 10.1186/s13195-019-0475-2
DO - 10.1186/s13195-019-0475-2
M3 - Article
C2 - 30902061
AN - SCOPUS:85063390025
VL - 11
JO - Breast Cancer Research
JF - Breast Cancer Research
SN - 1465-5411
IS - 1
M1 - 28
ER -