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

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Hishimoto, Akitoyo, Pletnikova, Olga, Lang, Doyle Lu, Troncoso, Juan C., Egan, Josephine M., Liu, Qing-Rong·2019·Alzheimer's Research & Therapy
DOI 10.1186/s13195-019-0475-2PMC PMC6429815
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Abstract

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. 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. 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. 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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  • NRXN3 is the isoform most consistently implicated in AD pathogenesis.

    “given that this isoform has been most consistently implicated in AD pathogenesis35–39.”

    From PLCG2 downregulation impairs synaptic function and increases Alzheimer’s disease hallmarks in neuronal cultures (2026) · cites this paper as [38]

    The Discussion (page not specified) explicitly implicates NRXN3 in AD, and the Results report reduced expression of several NRXN3 isoforms in AD brain samples. The paper does not establish that NRXN3 is the isoform most consistently implicated in AD pathogenesis relative to other isoforms. (LLM, conf=0.86)

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Authors
Hishimoto, A., Pletnikova, O., Lang, D. L., Troncoso, J. C., Egan, J. M., & Liu, Q.-R.
Affiliations
  • Kobe University (JP)
  • National Institutes of Health (US)
  • Johns Hopkins University (US)
Corresponding author
Liu, Qing-Rong
ORCID
Venue
Alzheimer's Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2019-03-21
Volume
11
Issue
1
Pages
28-28
ISSN
1758-9193 (ISSN-L)
DOI
10.1186/s13195-019-0475-2
PMC
PMC6429815
OpenAlex
W2938377404
Cited by
62
References
12
Citations by year
2026: 10 · 2025: 9 · 2024: 11 · 2023: 7 · 2022: 8 · 2021: 9 · 2020: 6 · 2019: 2
FWCI
4.29
Type
journal article
Language
en
Update notices
correction (2019-05-07)
Open access
Licence
Locations
  • Alzheimer s Research & Therapy (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Institutional Repositories DataBase (IRDB) (acceptedVersion, cc-by)
  • Kobe University Repository Kernel (Kobe University) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • IRP/NIA/NIH (AG-000291-11)
  • National Institutes of Health (P50AG05146)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
NRXN3, Alzheimer's disease, NLRP3 inflammasome, alternative splicing, APOE ε4, synaptic damage
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Encephalitis, Female, Haplotypes, Humans, Male, Nerve Tissue Proteins, Neurons, RNA, Messenger, Prefrontal Cortex, Protein Isoforms, Polymorphism, Single Nucleotide

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