Neurological Dysfunctions Associated with Altered BACE1-dependent Neuregulin-1 Signaling

Overview

Journal J Neurochem

Specialties Chemistry
Neurology

Date 2015 Oct 15

PMID 26465092

Citations 27

Authors

Xiangyou Hu

Qingyuan Fan

Hailong Hou

Riqiang Yan

Affiliations

Soon will be listed here.

Abstract

Inhibition of BACE1 is being pursued as a therapeutic target to treat patients suffering from Alzheimer's disease because BACE1 is the sole β-secretase that generates β-amyloid peptide. Knowledge regarding other cellular functions of BACE1 is therefore critical for the safe use of BACE1 inhibitors in human patients. Neuregulin-1 (Nrg1) is a BACE1 substrate and BACE1 cleavage of Nrg1 is critical for signaling functions in myelination, remyelination, synaptic plasticity, normal psychiatric behaviors, and maintenance of muscle spindles. This review summarizes the most recent discoveries associated with BACE1-dependent Nrg1 signaling in these areas. This body of knowledge will help to provide guidance for preventing unwanted Nrg1-based side effects following BACE1 inhibition in humans. To initiate its signaling cascade, membrane anchored Neuregulin (Nrg), mainly type I and III β1 Nrg1 isoforms and Nrg3, requires ectodomain shedding. BACE1 is one of such indispensable sheddases to release the functional Nrg signaling fragment. The dependence of Nrg on the cleavage by BACE1 is best manifested by disrupting the critical role of Nrg in the control of axonal myelination, schizophrenic behaviors as well as the formation and maintenance of muscle spindles.

Citing Articles

Contribution of amyloid deposition from oligodendrocytes in a mouse model of Alzheimer's disease.

Ishii A, Pathoulas J, MoustafaFathy Omar O, Ge Y, Yao A, Pantalena T Mol Neurodegener. 2024; 19(1):83.

PMID: 39548583 PMC: 11568619. DOI: 10.1186/s13024-024-00759-z.

Effects of Anti-Seizure Medication on Neuregulin-1 Gene and Protein in Patients with First-Episode Focal Epilepsy.

Zhao X, Huang G, Xie Z, Mo Y, Zhu H, Gao Y Neuropsychiatr Dis Treat. 2024; 20:837-844.

PMID: 38618155 PMC: 11012762. DOI: 10.2147/NDT.S438942.

Key brain cell interactions and contributions to the pathogenesis of Alzheimer's disease.

Saavedra J, Nascimento M, Liz M, Cardoso I Front Cell Dev Biol. 2022; 10:1036123.

PMID: 36523504 PMC: 9745159. DOI: 10.3389/fcell.2022.1036123.

Biological Mechanism-based Neurology and Psychiatry: A BACE1/2 and Downstream Pathway Model.

Hampel H, Caruso G, Nistico R, Piccioni G, Mercuri N, Giorgi F Curr Neuropharmacol. 2021; 21(1):31-53.

PMID: 34852743 PMC: 10193755. DOI: 10.2174/1570159X19666211201095701.

Role of Neuron and Glia in Alzheimer's Disease and Associated Vascular Dysfunction.

Bandyopadhyay S Front Aging Neurosci. 2021; 13:653334.

PMID: 34211387 PMC: 8239194. DOI: 10.3389/fnagi.2021.653334.

References

ODonovan K, Tourtellotte W, Millbrandt J, Baraban J . The EGR family of transcription-regulatory factors: progress at the interface of molecular and systems neuroscience. Trends Neurosci. 1999; 22(4):167-73. DOI: 10.1016/s0166-2236(98)01343-5. View

Yarnitzky T, Min L, Volk T . The Drosophila neuregulin homolog Vein mediates inductive interactions between myotubes and their epidermal attachment cells. Genes Dev. 1997; 11(20):2691-700. PMC: 316610. DOI: 10.1101/gad.11.20.2691. View

Mei L, Xiong W . Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev Neurosci. 2008; 9(6):437-52. PMC: 2682371. DOI: 10.1038/nrn2392. View

Huang Y, Won S, Ali D, Wang Q, Tanowitz M, Du Q . Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses. Neuron. 2000; 26(2):443-55. DOI: 10.1016/s0896-6273(00)81176-9. View

Mei L, Nave K . Neuregulin-ERBB signaling in the nervous system and neuropsychiatric diseases. Neuron. 2014; 83(1):27-49. PMC: 4189115. DOI: 10.1016/j.neuron.2014.06.007. View

Harrison P, Law A . Neuregulin 1 and schizophrenia: genetics, gene expression, and neurobiology. Biol Psychiatry. 2006; 60(2):132-40. DOI: 10.1016/j.biopsych.2005.11.002. View

Pitcher G, Kalia L, Ng D, Goodfellow N, Yee K, Lambe E . Schizophrenia susceptibility pathway neuregulin 1-ErbB4 suppresses Src upregulation of NMDA receptors. Nat Med. 2011; 17(4):470-8. PMC: 3264662. DOI: 10.1038/nm.2315. View

Amato D . Serotonin in antipsychotic drugs action. Behav Brain Res. 2014; 277:125-35. DOI: 10.1016/j.bbr.2014.07.025. View

Buonanno A, Kwon O, Yan L, Gonzalez C, Longart M, Hoffman D . Neuregulins and neuronal plasticity: possible relevance in schizophrenia. Novartis Found Symp. 2008; 289:165-77. DOI: 10.1002/9780470751251.ch13. View

10.

Vukadinovic Z . NMDA receptor hypofunction and the thalamus in schizophrenia. Physiol Behav. 2014; 131:156-9. DOI: 10.1016/j.physbeh.2014.04.038. View

11.

Emamian E, Hall D, Birnbaum M, Karayiorgou M, Gogos J . Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat Genet. 2004; 36(2):131-7. DOI: 10.1038/ng1296. View

12.

Vattemi G, Engel W, McFerrin J, Pastorino L, Buxbaum J, Askanas V . BACE1 and BACE2 in pathologic and normal human muscle. Exp Neurol. 2003; 179(2):150-8. DOI: 10.1016/s0014-4886(02)00025-0. View

13.

Emamian E . AKT/GSK3 signaling pathway and schizophrenia. Front Mol Neurosci. 2012; 5:33. PMC: 3304298. DOI: 10.3389/fnmol.2012.00033. View

14.

Fazzari P, Paternain A, Valiente M, Pla R, Lujan R, Lloyd K . Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling. Nature. 2010; 464(7293):1376-80. DOI: 10.1038/nature08928. View

15.

Suenaga A, Hatakeyama M, Ichikawa M, Yu X, Futatsugi N, Narumi T . Molecular dynamics, free energy, and SPR analyses of the interactions between the SH2 domain of Grb2 and ErbB phosphotyrosyl peptides. Biochemistry. 2003; 42(18):5195-200. DOI: 10.1021/bi034113h. View

16.

Kainulainen V, Sundvall M, Maatta J, Santiestevan E, Klagsbrun M, Elenius K . A natural ErbB4 isoform that does not activate phosphoinositide 3-kinase mediates proliferation but not survival or chemotaxis. J Biol Chem. 2000; 275(12):8641-9. DOI: 10.1074/jbc.275.12.8641. View

17.

Insel T . Rethinking schizophrenia. Nature. 2010; 468(7321):187-93. DOI: 10.1038/nature09552. View

18.

Sinha S, Anderson J, Barbour R, Basi G, Caccavello R, Davis D . Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature. 1999; 402(6761):537-40. DOI: 10.1038/990114. View

19.

Wang Y, Chen J, Chen M, Chen C, Lai I, Chen T . Neuregulin 3 genetic variations and susceptibility to schizophrenia in a Chinese population. Biol Psychiatry. 2008; 64(12):1093-6. DOI: 10.1016/j.biopsych.2008.07.012. View

20.

Okada M, Corfas G . Neuregulin1 downregulates postsynaptic GABAA receptors at the hippocampal inhibitory synapse. Hippocampus. 2004; 14(3):337-44. DOI: 10.1002/hipo.10185. View