A Peptide Motif Covering Splice Site B in Neuroligin-1 Binds to Aβ and Acts As a Neprilysin Inhibitor

Overview

Journal Mol Neurobiol

Specialties Molecular Biology
Neurology

Date 2024 Sep 11

PMID 39261388

Authors

Lene T Dietz

Katrin Pold

Balazs A Gyorffy

Alexander Zharkovsky

Jakob B Sorensen

Stanislava Pankratova

Oksana Dmytriyeva

Affiliations

Soon will be listed here.

Abstract

The most common cause of dementia among elderly people is Alzheimer's disease (AD). The typical symptom of AD is the decline of cognitive abilities, which is caused by loss of synaptic function. Amyloid-β (Aβ) oligomers play a significant role in the development of this synaptic dysfunction. Neuroligin-(NL)1 is a postsynaptic cell-adhesion molecule located in excitatory synapses and involved in the maintenance and modulation of synaptic contacts. A recent study has found that Aβ interacts with the soluble N-terminal fragment of NL1. The present study aimed to elucidate the role of NL1 in Aβ-induced neuropathology. Employing surface plasmon resonance and competitive ELISA, we confirmed the high-affinity binding of NL1 to the Aβ peptide. We also identified a sequence motif representing the NL1-binding site for the Aβ peptide and showed that a synthetic peptide modeled after this motif, termed neurolide, binds to the Aβ peptide with high affinity, comparable to the NL1-Aβ interaction. To assess the effect of neurolide in vivo, wild-type and 5XFAD mice were subcutaneously treated with this peptide for 10 weeks. We observed an increase in Aβ plaque formation in the cortex of neurolide-treated 5XFAD mice. Furthermore, we showed that neurolide reduces the activity of neprilysin, the predominant Aβ-degrading enzyme in the brain. Accordingly, we suggest that neurolide is the NL1-binding site for Aβ peptide, and acts as an inhibitor of neprilysin activity. Based on these data, we confirm the involvement of NL1 in the development of AD and suggest a mechanism for NL1-induced Aβ plaque formation.

References

Cline E, Bicca M, Viola K, Klein W . The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade. J Alzheimers Dis. 2018; 64(s1):S567-S610. PMC: 6004937. DOI: 10.3233/JAD-179941. View

Pozueta J, Lefort R, Shelanski M . Synaptic changes in Alzheimer's disease and its models. Neuroscience. 2012; 251:51-65. DOI: 10.1016/j.neuroscience.2012.05.050. View

Serrano-Pozo A, Frosch M, Masliah E, Hyman B . Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med. 2012; 1(1):a006189. PMC: 3234452. DOI: 10.1101/cshperspect.a006189. View

De Strooper B, Iwatsubo T, Wolfe M . Presenilins and γ-secretase: structure, function, and role in Alzheimer Disease. Cold Spring Harb Perspect Med. 2012; 2(1):a006304. PMC: 3253024. DOI: 10.1101/cshperspect.a006304. View

Huttenrauch M, Baches S, Gerth J, Bayer T, Weggen S, Wirths O . Neprilysin deficiency alters the neuropathological and behavioral phenotype in the 5XFAD mouse model of Alzheimer's disease. J Alzheimers Dis. 2014; 44(4):1291-302. DOI: 10.3233/JAD-142463. View

Ylisaukko-Oja T, Rehnstrom K, Auranen M, Vanhala R, Alen R, Kempas E . Analysis of four neuroligin genes as candidates for autism. Eur J Hum Genet. 2005; 13(12):1285-92. DOI: 10.1038/sj.ejhg.5201474. View

Ichtchenko K, Nguyen T, Sudhof T . Structures, alternative splicing, and neurexin binding of multiple neuroligins. J Biol Chem. 1996; 271(5):2676-82. DOI: 10.1074/jbc.271.5.2676. View

Budreck E, Kwon O, Jung J, Baudouin S, Thommen A, Kim H . Neuroligin-1 controls synaptic abundance of NMDA-type glutamate receptors through extracellular coupling. Proc Natl Acad Sci U S A. 2012; 110(2):725-30. PMC: 3545745. DOI: 10.1073/pnas.1214718110. View

Giannone G, Mondin M, Grillo-Bosch D, Tessier B, Saint-Michel E, Czondor K . Neurexin-1β binding to neuroligin-1 triggers the preferential recruitment of PSD-95 versus gephyrin through tyrosine phosphorylation of neuroligin-1. Cell Rep. 2013; 3(6):1996-2007. DOI: 10.1016/j.celrep.2013.05.013. View

10.

Iida J, Hirabayashi S, Sato Y, Hata Y . Synaptic scaffolding molecule is involved in the synaptic clustering of neuroligin. Mol Cell Neurosci. 2004; 27(4):497-508. DOI: 10.1016/j.mcn.2004.08.006. View

11.

Zhang B, Sudhof T . Neuroligins Are Selectively Essential for NMDAR Signaling in Cerebellar Stellate Interneurons. J Neurosci. 2016; 36(35):9070-83. PMC: 5005720. DOI: 10.1523/JNEUROSCI.1356-16.2016. View

12.

Elegheert J, Cvetkovska V, Clayton A, Heroven C, Vennekens K, Smukowski S . Structural Mechanism for Modulation of Synaptic Neuroligin-Neurexin Signaling by MDGA Proteins. Neuron. 2017; 95(4):896-913.e10. PMC: 5563082. DOI: 10.1016/j.neuron.2017.07.040. View

13.

Molumby M, Anderson R, Newbold D, Koblesky N, Garrett A, Schreiner D . γ-Protocadherins Interact with Neuroligin-1 and Negatively Regulate Dendritic Spine Morphogenesis. Cell Rep. 2017; 18(11):2702-2714. PMC: 5418859. DOI: 10.1016/j.celrep.2017.02.060. View

14.

Xu J, Xiao N, Xia J . Thrombospondin 1 accelerates synaptogenesis in hippocampal neurons through neuroligin 1. Nat Neurosci. 2009; 13(1):22-4. DOI: 10.1038/nn.2459. View

15.

Hoffman R, Jennings L, Tsigelny I, Comoletti D, Flynn R, Sudhof T . Structural characterization of recombinant soluble rat neuroligin 1: mapping of secondary structure and glycosylation by mass spectrometry. Biochemistry. 2004; 43(6):1496-506. DOI: 10.1021/bi035278t. View

16.

Comoletti D, Flynn R, Jennings L, Chubykin A, Matsumura T, Hasegawa H . Characterization of the interaction of a recombinant soluble neuroligin-1 with neurexin-1beta. J Biol Chem. 2003; 278(50):50497-505. DOI: 10.1074/jbc.M306803200. View

17.

Peixoto R, Kunz P, Kwon H, Mabb A, Sabatini B, Philpot B . Transsynaptic signaling by activity-dependent cleavage of neuroligin-1. Neuron. 2012; 76(2):396-409. PMC: 3783515. DOI: 10.1016/j.neuron.2012.07.006. View

18.

Suzuki K, Hayashi Y, Nakahara S, Kumazaki H, Prox J, Horiuchi K . Activity-dependent proteolytic cleavage of neuroligin-1. Neuron. 2012; 76(2):410-22. DOI: 10.1016/j.neuron.2012.10.003. View

19.

Gjorlund M, Carlsen E, Konig A, Dmytrieva O, Petersen A, Jacobsen J . Soluble Ectodomain of Neuroligin 1 Decreases Synaptic Activity by Activating Metabotropic Glutamate Receptor 2. Front Mol Neurosci. 2017; 10:116. PMC: 5413576. DOI: 10.3389/fnmol.2017.00116. View

20.

Dinamarca M, Weinstein D, Monasterio O, Inestrosa N . The synaptic protein neuroligin-1 interacts with the amyloid β-peptide. Is there a role in Alzheimer's disease?. Biochemistry. 2011; 50(38):8127-37. DOI: 10.1021/bi201246t. View