Abstract
BackgroundSynaptic 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.MethodsWe 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 χ2 tests, and ISH signals were analyzed by FISH v1.0 module of Indica Labs HALO software.ResultsWe 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.ConclusionsWe 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.
Highlights
Synaptic damage precedes neuron death in Alzheimer’s disease (AD)
Neurexin genes are among the largest genes in the human genome, and the three mammalian neurexin genes NRXN1, NRXN2, and NRXN3 each display differential splicing events that provide thousands of neurexin isoforms on a background of longer α-neurexin and shorter β-neurexin that arise from the use of alternative promoters [11]
The β-neurexin acts as a brake for endocannabinoid 2-AG (2-arachidonoylglycerol) synthesis that retrogradely regulates presynaptic cannabinoid receptor 1 (CB1R)-mediated depolarization-induced suppression of excitation on AMPA and NMDA receptors that are involved in excitatory postsynaptic currents (EPSCs) [22]
Summary
NRXN1, NRXN2, and NRXN3, are presynaptic adhesion molecules that specify neuron synapses and regulate neurotransmitter release. Neurexins were discovered as α-latrotoxin (venom of black widow spider) receptors [9] and function as presynaptic cell adhesion molecules [10] that help to regulate the release of neurotransmitters, specify, and stabilize classical synapses, including the glutamatergic synapses that provide a focus for research in AD [1, 2]. Α-neurexins are coupled to presynaptic calcium channels to regulate neurotransmitter release [13] and interact with postsynaptic neuroligins, leucine-rich repeat transmembrane proteins (LRRTMs), calsyntenins (CLSTN), α-dystroglycan (DAG1), GABAA-receptors (GABRAs), latrophilins (ADGRLs), cerebellin (CBLN)-glutamate dehydrogenase (GLUD) complexes, synaptic cleft secreted neurexophilins (NXPHs), and intracellular PDZ-binding proteins [14, 15]. Recent data identify roles of neurexin isoforms in several complex neuropsychiatric phenotypes that include autism [24,25,26], addiction [20, 27, 28], and schizophrenia [29, 30]
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