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ErbB4 deficiency exacerbates olfactory dysfunction in an early-stage Alzheimer’s disease mouse model

Acta Pharmacologica Sinica volume 45, pages 2497–2512 (2024)Cite this article

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Abstract

Olfactory dysfunction is increasingly recognized as an early indicator of Alzheimer’s disease (AD). Aberrations in GABAergic function and the excitatory/inhibitory (E/I) balance within the olfactory bulb (OB) have been implicated in olfactory impairment during the initial stages of AD. While the neuregulin 1 (NRG1)/ErbB4 signaling pathway is known to regulate GABAergic transmission in the brain and is associated with various neuropsychiatric disorders, its specific role in early AD-related olfactory impairment remains incompletely understood. This study demonstrated that olfactory dysfunction preceded cognitive decline in young adult APP/PS1 mice and was characterized by reduced levels of NRG1 and ErbB4 in the OB. Further investigation revealed that deletion of ErbB4 in parvalbumin interneurons reduced GABAergic transmission and increased hyperexcitability in mitral and tufted cells (M/Ts) in the OB, thereby accelerating olfactory dysfunction in young adult APP/PS1 mice. Additionally, ErbB4 deficiency was associated with increased accumulation of Aβ and BACE1-mediated cleavage of APP, along with enhanced CDK5 signaling in the OB. NRG1 infusion into the OB was found to enhance GABAergic transmission in M/Ts and alleviate olfactory dysfunction in young adult APP/PS1 mice. These findings underscore the critical role of NRG1/ErbB4 signaling in regulating GABAergic transmission and E/I balance within the OB, contributing to olfactory impairment in young adult APP/PS1 mice, and provide novel insights for early intervention strategies in AD.

This work has shown that ErbB4 deficiency increased the burden of Aβ, impaired GABAergic transmission, and disrupted the E/I balance of mitral and tufted cells (M/Ts) in the OB, ultimately resulting in olfactory dysfunction in young adult APP/PS1 mice. NRG1 could enhance GABAergic transmission, rescue E/I imbalance in M/Ts, and alleviate olfactory dysfunction in young adult APP/PS1 mice. OB: olfactory bulb, E/I: excitation/inhibition, Pr: probability of release, PV: parvalbumin interneurons, Aβ: β-amyloid, GABA: gamma-aminobutyric acid.

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Fig. 1: Impaired olfactory behavior in 3-month-old APP/PS1 mice.
Fig. 2: Hyperexcitability and defective GABAergic transmission of M/Ts in the OB in 3-month-old APP/PS1 mice.
Fig. 3: Reduced NRG1 and ErbB4 expression in the OB of APP/PS1 mice.
Fig. 4: ErbB4 deficiency in parvalbumin interneurons accelerated olfactory dysfunction and reduced dendritic spines and synapses of OB in 3-month-old APP/PS1 mice.
Fig. 5: ErbB4 deficiency exacerbated hyperexcitability and impaired GABAergic transmission of M/Ts in the OB in APP/PS1 mice.
Fig. 6: ErbB4 deficiency exacerbated Aβ deposition and BACE1-mediated cleavage of APP in the OB in APP/PS1 mice.
Fig. 7: ErbB4 deficiency correlated with increased CDK5 signaling in the OB of young adult APP/PS1 mice.
Fig. 8: OB infusion of NRG1 alleviated olfactory dysfunction and promoted the GABAergic transmission of M/Ts in the OB in APP/PS1 mice.

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  • 26 July 2024

    In the originally published article the ESM file has been omitted. This has been corrected.

References

  1. The Alzheimer’s Association. 2022 Alzheimer’s disease facts and figures. Alzheimers Dement. 2022;18:700–89.

  2. Piton M, Hirtz C, Desmetz C, Milhau J, Lajoix AD, Bennys K, et al. Alzheimer’s disease: advances in drug development. J Alzheimers Dis. 2018;65:3–13.

    Article  PubMed  Google Scholar 

  3. Dan X, Wechter N, Gray S, Mohanty JG, Croteau DL, Bohr VA. Olfactory dysfunction in aging and neurodegenerative diseases. Ageing Res Rev. 2021;70:101416.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bathini P, Brai E, Auber LA. Olfactory dysfunction in the pathophysiological continuum of dementia. Ageing Res Rev. 2019;55:100956.

    Article  PubMed  Google Scholar 

  5. Murphy C. Olfactory and other sensory impairments in Alzheimer disease. Nat Rev Neurol. 2019;15:11–24.

    Article  CAS  PubMed  Google Scholar 

  6. Yan Y, Aierken A, Wang C, Song D, Ni J, Wang Z, et al. A potential biomarker of preclinical Alzheimer’s disease: the olfactory dysfunction and its pathogenesis-based neural circuitry impairments. Neurosci Biobehav Rev. 2022;132:857–69.

    Article  CAS  PubMed  Google Scholar 

  7. Mori K, Sakano H. Olfactory circuitry and behavioral decisions. Annu Rev Physiol. 2021;83:231–56.

    Article  CAS  PubMed  Google Scholar 

  8. Imamura F, Ito A, LaFever BJ. Subpopulations of projection neurons in the olfactory bulb. Front Neural Circuits. 2020;14:561822.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Jones S, Zylberberg J, Schoppa N. Cellular and synaptic mechanisms that differentiate mitral cells and superficial tufted cells into parallel output channels in the olfactory bulb. Front Cell Neurosci. 2020;14:614377.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hu B, Geng C, Guo F, Liu Y, Zong YC, Hou XY. GABAA receptor agonist muscimol rescues inhibitory microcircuit defects in the olfactory bulb and improves olfactory function in APP/PS1 transgenic mice. Neurobiol Aging. 2021;108:47–57.

    Article  CAS  PubMed  Google Scholar 

  11. Wesson DW, Levy E, Nixon RA, Wilson DA. Olfactory dysfunction correlates with amyloid-beta burden in an Alzheimer’s disease mouse model. J Neurosci. 2010;30:505–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wu N, Rao X, Gao Y, Wang J, Xu F. Amyloid-beta deposition and olfactory dysfunction in an Alzheimer’s disease model. J Alzheimers Dis. 2013;37:699–712.

    Article  CAS  PubMed  Google Scholar 

  13. Li W, Li S, Shen L, Wang J, Wu X, Li J, et al. Impairment of dendrodendritic inhibition in the olfactory bulb of APP/PS1 mice. Front Aging Neurosci. 2019;11:2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wang MD, Zhang S, Liu XY, Wang PP, Zhu YF, Zhu JR, et al. Salvianolic acid B ameliorates retinal deficits in an early-stage Alzheimer’s disease mouse model through downregulating BACE1 and Aβ generation. Acta Pharmacol Sin. 2023;44:2151–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. McDade E, Voytyuk I, Aisen P, Bateman RJ, Carrillo MC, De Strooper B, et al. The case for low-level BACE1 inhibition for the prevention of Alzheimer disease. Nat Rev Neurol. 2021;17:703–14.

    Article  PubMed  Google Scholar 

  16. Yoo SJ, Lee JH, Kim SY, Son G, Kim JY, Cho B, et al. Differential spatial expression of peripheral olfactory neuron-derived BACE1 induces olfactory impairment by region-specific accumulation of beta-amyloid oligomer. Cell Death Dis. 2017;8:e2977.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhang XM, Xiong K, Cai Y, Cai H, Luo XG, Feng JC, et al. Functional deprivation promotes amyloid plaque pathogenesis in Tg2576 mouse olfactory bulb and piriform cortex. Eur J Neurosci. 2010;31:710–21.

    Article  PubMed  PubMed Central  Google Scholar 

  18. De la Rosa Prieto C, Saiz Sanchez D, Ubeda Banon I, Flores Cuadrado A, Martinez Marcos A. Neurogenesis, neurodegeneration, interneuron vulnerability, and amyloid-β in the olfactory bulb of APP/PS1 mouse model of Alzheimer’s disease. Front Neurosci. 2016;10:227.

    PubMed  PubMed Central  Google Scholar 

  19. Wesson DW, Borkowski AH, Landreth GE, Nixon RA, Levy E, Wilson DA. Sensory network dysfunction, behavioral impairments, and their reversibility in an Alzheimer’s β-amyloidosis mouse model. J Neurosci. 2011;31:15962–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hu B, Geng C, Hou XY. Oligomeric amyloid-beta peptide disrupts olfactory information output by impairment of local inhibitory circuits in rat olfactory bulb. Neurobiol Aging. 2017;51:113–21.

    Article  CAS  PubMed  Google Scholar 

  21. Batra S, Jahan S, Ashraf A, Alharby B, Jawaid T, Islam A, et al. A review on cyclin-dependent kinase 5: An emerging drug target for neurodegenerative diseases. Int J Biol Macromol. 2023;230:123259.

    Article  CAS  PubMed  Google Scholar 

  22. Pao PC, Tsai LH. Three decades of Cdk5. J Biomed Sci. 2021;28:79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lu TT, Wan C, Yang W, Cai Z. Role of Cdk5 in amyloid-beta pathology of Alzheimer’s disease. Curr Alzheimer Res. 2019;16:1206–15.

    Article  CAS  PubMed  Google Scholar 

  24. Maitra S, Vincent B. Cdk5-p25 as a key element linking amyloid and tau pathologies in Alzheimer’s disease: mechanisms and possible therapeutic interventions. Life Sci. 2022;308:120986.

    Article  CAS  PubMed  Google Scholar 

  25. Mei L, Xiong WC. Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev Neurosci. 2008;9:437–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chen YJ, Zhang M, Yin DM, Wen L, Ting A, Wang P, et al. ErbB4 in parvalbumin-positive interneurons is critical for neuregulin 1 regulation of long-term potentiation. Proc Natl Acad Sci USA. 2010;107:21818–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhang H, Zhang L, Zhou D, He X, Wang D, Pan H, et al. Ablating ErbB4 in PV neurons attenuates synaptic and cognitive deficits in an animal model of Alzheimer’s disease. Neurobiol Dis. 2017;106:171–80.

    Article  CAS  PubMed  Google Scholar 

  28. Robinson HL, Tan Z, Santiago Marrero I, Arzola EP, Dong TV, Xiong WC, et al. Neuregulin 1 and ErbB4 kinase actively regulate sharp wave ripples in the hippocampus. J Neurosci. 2022;42:390–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang H, Liu F, Chen W, Sun X, Cui W, Dong Z, et al. Genetic recovery of ErbB4 in adulthood partially restores brain functions in null mice. Proc Natl Acad Sci USA. 2018;115:13105–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Li B, Woo RS, Mei L, Malinow R. The neuregulin-1 receptor erbB4 controls glutamatergic synapse maturation and plasticity. Neuron. 2007;54:583–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Luo B, Liu Z, Lin D, Chen W, Ren D, Yu Z, et al. ErbB4 promotes inhibitory synapse formation by cell adhesion, independent of its kinase activity. Transl Psychiatry. 2021;11:361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wen L, Lu YS, Zhu XH, Li XM, Woo RS, Chen YJ, et al. Neuregulin 1 regulates pyramidal neuron activity via ErbB4 in parvalbumin-positive interneurons. Proc Natl Acad Sci USA. 2009;107:1211–6.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Gao YZ, Wu XM, Zhou ZQ, Liu PM, Yang JJ, Ji MH. Dysfunction of NRG1/ErbB4 signaling in the hippocampus might mediate long-term memory decline after systemic inflammation. Mol Neurobiol. 2023;60:3210–26.

    Article  CAS  PubMed  Google Scholar 

  34. Yoo JY, Kim HB, Baik TK, Lee JH, Woo RS. Neuregulin 1/ErbB4/Akt signaling attenuates cytotoxicity mediated by the APP-CT31 fragment of amyloid precursor protein. Exp Mol Pathol. 2021;120:104622.

    Article  CAS  PubMed  Google Scholar 

  35. Tian J, Geng F, Gao F, Chen YH, Liu JH, Wu JL, et al. Down-regulation of Neuregulin1/ErbB4 signaling in the hippocampus is critical for learning and memory. Mol Neurobiol. 2017;54:3976–87.

    Article  CAS  PubMed  Google Scholar 

  36. Tan Z, Liu Z, Liu Y, Liu F, Robinson H, Lin TW, et al. An ErbB4-positive neuronal network in the olfactory bulb for olfaction. J Neurosci. 2022;42:6518–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lu Y, Sun XD, Hou FQ, Bi LL, Yin DM, Liu F, et al. Maintenance of GABAergic activity by neuregulin 1-ErbB4 in amygdala for fear memory. Neuron. 2014;84:835–46.

    Article  CAS  PubMed  Google Scholar 

  38. Li KX, Lu YM, Xu ZH, Zhang J, Zhu JM, Zhang JM, et al. Neuregulin 1 regulates excitability of fast-spiking neurons through Kv1.1 and acts in epilepsy. Nat Neurosci. 2011;15:267–73.

    Article  PubMed  Google Scholar 

  39. Liu XY, Wang K, Deng XH, Wei YH, Rui Guo R, Liu SF, et al. Amelioration of olfactory dysfunction in a mouse model of Parkinson’s disease via enhancing GABAergic signaling. Cell Biosci. 2023;13:101.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Dewan A, Pacifico R, Zhan R, Rinberg D, Bozza T. Non-redundant coding of aversive odours in the main olfactory pathway. Nature. 2013;497:486–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhu Y, Demidov ON, Goh AM, Virshup DM, Lane DP, Bulavin DV. Phosphatase WIP1 regulates adult neurogenesis and WNT signaling during aging. J Clin Invest. 2014;124:3263–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Liu J, Liu C, Zhang J, Zhang Y, Liu K, Song JX, et al. A Self-assembled alpha-synuclein nanoscavenger for Parkinson’s disease. ACS Nano. 2020;14:1533–49.

    Article  CAS  PubMed  Google Scholar 

  43. Yin DM, Sun XD, Bean JC, Lin TW, Sathyamurthy A, Xiong WC, et al. Regulation of spine formation by ErbB4 in PV-positive interneurons. J Neurosci. 2013;33:19295–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wen L, Tang FL, Hong Y, Luo SW, Wang CL, He W, et al. VPS35 haploinsufficiency increases Alzheimer’s disease neuropathology. J Cell Biol. 2011;195:765–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhang HL, Zhao B, Yang P, Du YQ, Han W, Xu J, et al. Steroid receptor coactivator 3 regulates synaptic plasticity and hippocampus-dependent memory. Neurosci Bull. 2021;37:1645–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Bi LL, Sun XD, Zhang J, Lu YS, Chen YH, Wang J, et al. Amygdala NRG1–ErbB4 is critical for the modulation of anxiety-like behaviors. Neuropsychopharmacology. 2015;40:974–86.

    Article  CAS  PubMed  Google Scholar 

  47. Lepousez G, Mouret A, Loudes C, Epelbaum J, Viollet C. Somatostatin contributes to in vivo gamma oscillation modulation and odor discrimination in the olfactory bulb. J Neurosci. 2010;30:870–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Laukka EJ, Ekstrom I, Larsson M, Grande G, Fratiglioni L, Rizzuto D. Markers of olfactory dysfunction and progression to dementia: A 12-year population-based study. Alzheimers Dement. 2023;19:3019–27.

    Article  CAS  PubMed  Google Scholar 

  49. LaFever BJ, Imamura F. Effects of nasal inflammation on the olfactory bulb. J Neuroinflammation. 2022;19:294.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Ohm TG, Braak H. Olfactory bulb changes in Alzheimer’s disease. Acta Neuropathol. 1987;73:365–9.

    Article  CAS  PubMed  Google Scholar 

  51. Struble RG, Clark HB. Olfactory bulb lesions in Alzheimer’s disease. Neurobiol Aging. 1992;13:469–73.

    Article  CAS  PubMed  Google Scholar 

  52. Thomann PA, Dos Santos V, Toro P, Schönknecht P, Essig M, Schröder J. Reduced olfactory bulb and tract volume in early Alzheimer’s disease–a MRI study. Neurobiol Aging. 2009;30:838–41.

    Article  PubMed  Google Scholar 

  53. Chen M, Chen Y, Huo Q, Wang L, Tan S, Misrani A, et al. Enhancing GABAergic signaling ameliorates aberrant gamma oscillations of olfactory bulb in AD mouse models. Mol Neurodegener. 2021;16:14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Min SS, An J, Lee JH, Seol GH, Im JH, Kim HS, et al. Neuregulin-1 prevents amyloid β-induced impairment of long-term potentiation in hippocampal slices via ErbB4. Neurosci Lett. 2011;505:6–9.

    Article  CAS  PubMed  Google Scholar 

  55. Ryu J, Hong BH, Kim YJ, Yang EJ, Choi M, Kim HS, et al. Neuregulin-1 attenuates cognitive function impairments in a transgenic mouse model of Alzheimer’s disease. Cell Death Dis. 2016;7:e2117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kim YJ, Yoo JY, Kim OS, Kim HB, Ryu J, Kim HS, et al. Neuregulin 1 regulates amyloid precursor protein cell surface expression and non-amyloidogenic processing. J Pharmacol Sci. 2018;137:146–53.

    Article  CAS  PubMed  Google Scholar 

  57. Maestu F, de Haan W, Busche MA, DeFelipe J. Neuronal excitation/inhibition imbalance: core element of a translational perspective on Alzheimer pathophysiology. Ageing Res Rev. 2021;69:101372.

    Article  CAS  PubMed  Google Scholar 

  58. Bi D, Wen L, Wu Z, Shen Y. GABAergic dysfunction in excitatory and inhibitory (E/I) imbalance drives the pathogenesis of Alzheimer’s disease. Alzheimers Dement. 2020;16:1312–29.

    Article  PubMed  Google Scholar 

  59. Breton Provencher V, Bakhshetyan K, Hardy D, Bammann RR, Cavarretta F, Snapyan M, et al. Principal cell activity induces spine relocation of adult-born interneurons in the olfactory bulb. Nat Commun. 2016;7:12659.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Lin TW, Tan ZB, Barik A, Yin DM, Brudvik E, Wang HS, et al. Regulation of synapse development by vgat deletion from ErbB4-positive interneurons. J Neurosci. 2018;38:2533–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Liu G, Froudarakis E, Patel JM, Kochukov MY, Pekarek B, Hunt PJ, et al. Target specific functions of EPL interneurons in olfactory circuits. Nat Commun. 2019;10:3369.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Saiz Sanchez D, Flores Cuadrado A, Ubeda Bañon I, de la Rosa Prieto C, Martinez Marcos A. Interneurons in the human olfactory system in Alzheimer’s disease. Exp Neurol. 2016;276:13–21.

    Article  CAS  PubMed  Google Scholar 

  63. Jimenez Balado J, Eich TS. GABAergic dysfunction, neural network hyperactivity and memory impairments in human aging and Alzheimer’s disease. Semin Cell Dev Biol. 2021;116:146–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Xu Y, Zhao M, Han Y, Zhang H. GABAergic inhibitory interneuron deficits in alzheimer’s disease: implications for treatment. Front Neurosci. 2020;14:660.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Funamoto S, Tagami S, Okochi M, Morishima Kawashima M. Successive cleavage of β-amyloid precursor protein by γ-secretase. Semin Cell Dev Biol. 2020;105:64–74.

    Article  CAS  PubMed  Google Scholar 

  66. Kiss E, Groeneweg F, Gorgas K, Schlicksupp A, Kins S, Kirsch J, et al. Amyloid-β fosters p35/CDK5 signaling contributing to changes of inhibitory synapses in early stages of cerebral amyloidosis. J Alzheimers Dis. 2020;74:1167–87.

    Article  CAS  PubMed  Google Scholar 

  67. Sadleir KR, Vassar R. Cdk5 protein inhibition and Aβ42 increase BACE1 protein level in primary neurons by a post-transcriptional mechanism. J Biol Chem. 2012;287:7224–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Mei L, Nave KA. Neuregulin-ERBB signaling in the nervous system and neuropsychiatric diseases. Neuron. 2014;83:27–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Rudenko A, Seo J, Hu J, Su SC, de Anda FC, Durak O, et al. Loss of cyclin-dependent kinase 5 from parvalbumin interneurons leads to hyperinhibition, decreased anxiety, and memory impairment. J Neurosci. 2015;35:2372–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Rakic S, Kanatani S, Hunt D, Faux C, Cariboni A, Chiara F, et al. Cdk5 phosphorylation of ErbB4 is required for tangential migration of cortical interneurons. Cereb Cortex. 2015;25:991–1003.

    Article  PubMed  Google Scholar 

  71. Kim SH, Ryan TA. CDK5 serves as a major control point in neurotransmitter release. Neuron. 2010;67:797–809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Kim SH, Ryan TA. Balance of calcineurin Aα and CDK5 activities sets release probability at nerve terminals. J Neurosci. 2013;33:8937–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Thanks to Prof. Lin Mei (Chinese Institutes for Medical Research) and Prof. Xiao-ming Li (Zhejiang University) for the generous gift of loxp-flanked ErbB4 mice and PV-Cre mice. Thanks to Prof. Jie Zhang (Xiamen University) for kindly providing antibodies of CDK5 and p35.

Funding

The work was supported by the National Natural Science Foundation of China (82274301 and 81774377), the Natural Science Foundation of Fujian Province of China (2021J01019), the National Key Research and Development Program of China (2016YFC1305903) and the Program for New Century Excellent Talents in University of China (NCET-13-0505).

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  1. These authors contributed equally: Xian-hua Deng, Xing-yang Liu, Yi-hua Wei

Authors and Affiliations

  1. Center for Brain Sciences, The First Affiliated Hospital of Xiamen University, State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, 361000, China

    Xian-hua Deng, Xing-yang Liu, Yi-hua Wei, Ke Wang, Jun-rong Zhu, Jia-jun Zhong, Jing-yuan Zheng, Rui Guo, Yi-fan Zhu, Qiu-hong Ye, Meng-dan Wang, Ying-jie Chen, Ze-xu Chen, Shu-qiong Huang, Chong-shan Lv & Lei Wen

  2. Department of Neurology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, 310006, China

    Xian-hua Deng, Xing-yang Liu, Yi-hua Wei, Ke Wang & Guo-qing Zheng

  3. Zhongshan Hospital, School of Medicine, Xiamen University, Xiamen, 361000, China

    Jian-quan He & Sui-feng Liu

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Contributions

LW designed the experiments, supervised the project. XHD and XYL wrote the manuscript, LW, GQZ and SFL edited the manuscript. XHD, YHW and KW performed the Western blotting experiments and analyzed the data. XHD, XYL, YHW and RG performed the electrophysiological experiments. JJZ and JYZ analyzed the electrophysiological data. JRZ, MDW, and QHY performed the immunostaining., YHW, YFZ, JYZ and JJZ helped with animal breeding, behavioral experiments as well as data analysis. YJC, JQH, ZXC, SQH and CSL have directly accessed and verified the underlying data reported in the manuscript. All authors read and approved the final manuscript.

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Correspondence to Guo-qing Zheng, Sui-feng Liu or Lei Wen.

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Deng, Xh., Liu, Xy., Wei, Yh. et al. ErbB4 deficiency exacerbates olfactory dysfunction in an early-stage Alzheimer’s disease mouse model. Acta Pharmacol Sin 45, 2497–2512 (2024). https://doi.org/10.1038/s41401-024-01332-6

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