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Journal of Neuroinflammation

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Open Access 01-12-2022 | Research

Synaptic loss and progression in mice infected with Angiostrongylus cantonensis in the early stage

Authors: Kai-Yuan Jhan, Pi-Kai Chang, Chien-Ju Cheng, Shih-Ming Jung, Lian-Chen Wang

Published in: Journal of Neuroinflammation | Issue 1/2022

Abstract

Background

Angiostrongylus cantonensis is also known as rat lungworm. Infection with this parasite is a zoonosis that can cause eosinophilic meningitis and/or eosinophilic meningoencephalitis in humans and may lead to fatal outcomes in severe cases. In this study, we explored the mechanisms of the impairments in the cognitive functions of mice infected with A. cantonensis.

Methods

In infected mice with different infective intensities at different timepoint postinfection, loss and recovery of cognitive functions such as learning and memory abilities were determined. Neuronal death and damage to synaptic structures were analyzed by Western blotting and IHC in infected mice with different infection intensities at different timepoint postinfection.

Results

The results of behavioral tests, pathological examinations, and Golgi staining showed that nerve damage caused by infection in mice occurred earlier than pathological changes of the brain. BDNF was expressed on 14 day post-infection. Cleaved caspase-3 increased significantly in the late stage of infection. However, IHC on NeuN indicated that no significant changes in the number of neurons were found between the infected and uninfected groups.

Conclusions

The synaptic loss caused by the infection of A. cantonensis provides a possible explanation for the impairment of cognitive functions in mice. The loss of cognitive functions may occur before severe immunological and pathological changes in the infected host.

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Alicata JE. Historical summary of Angiostrongyliasis cantonensis as a new parasitic disease of man. Bull Soc Pathol Exot Filiales. 1988;81:766–8.PubMed

Alicata JE. The discovery of Angiostrongylus cantonensis as a cause of human eosinophilic meningitis. Parasitol Today. 1991;7:151–3.CrossRefPubMed

Nomura S, Lin H. First clinical case of Haemostrongylus ratti (Japennnese text). Taiwan No Ikai. 1945;3:589–92.

Wang QP, Lai DH, Zhu XQ, Chen XG, Lun ZR. Human angiostrongyliasis. Lancet Infect Dis. 2008;8:621–30.CrossRefPubMed

Wang QP, Wu ZD, Wei J, Owen RL, Lun ZR. Human Angiostrongylus cantonensis: an update. Eur J Clin Microbiol Infect Dis. 2012;31:389–95.CrossRefPubMed

Barratt J, Chan D, Sandaradura I, Malik R, Spielman D, Lee R, Marriott D, Harkness J, Ellis J, Stark D. Angiostrongylus cantonensis: a review of its distribution, molecular biology and clinical significance as a human pathogen. Parasitology. 2016;143:1087–118.CrossRefPubMed

Kramer KJ, Posner J, Gosnell WL. Role of gastropod mucus in the transmission of Angiostrongylus cantonensis, a potentially serious neurological infection. ACS Chem Neurosci. 2018;9:629–32.CrossRefPubMed

Mahncke HW, Bronstone A, Merzenich MM. Brain plasticity and functional losses in the aged: scientific bases for a novel intervention. Prog Brain Res. 2006;157:81–109.CrossRefPubMed

Schultz W. Neuronal reward and decision signals: from theories to data. Physiol Rev. 2015;95:853–951.CrossRefPubMedPubMedCentral

10.

Loot G, Brosse S, Lek S, Guégan JF. Behaviour of roach (Rutilus rutilus L.) altered by Ligula intestinalis (Cestoda: Pseudophyllidea): a field demonstration. Freshwater Biol. 2001;46:1219–27.CrossRef

11.

Paris L, El Alaoui H, Delbac F, Diogon M. Effects of the gut parasite Nosema ceranae on honey bee physiology and behavior. Curr Opin Insect Sci. 2018;26:149–54.CrossRefPubMed

12.

Cox DM, Holland CV. Relationship between three intensity levels of Toxocara canis larvae in the brain and effects on exploration, anxiety, learning and memory in the murine host. J Helminthol. 2001;75:33–41.CrossRefPubMed

13.

Wang HL, Bao AY, Wang GH, Jiang MS, Liu ZC, Dong HF, Guo Y. Effect of chronic Toxoplasma infection on the spatial learning and memory capability in mice. Zhongguo Ji Sheng Chong Xue Yu Ji Sheng Chong Bing Za Zhi. 2006;24:114–8.PubMed

14.

Zhang MY, Xu YY, Pan T, Hu Y, Limpanont Y, Huang P, Okanurak K, Wu YQ, Dekumyoy P, Zhou HG, Watthanakulpanich D, Wu ZD, Wang Z, Lv ZY. Apoptosis and necroptosis of mouse hippocampal and parenchymal astrocytes, microglia and neurons caused by Angiostrongylus cantonensis infection. Parasit Vectors. 2017;10:611.CrossRef

15.

Chen X, Oppenheim JJ, Howard OM. BALB/c mice have more CD4+CD25+ T regulatory cells and show greater susceptibility to suppression of their CD4+CD25- responder T cells than C57BL/6 mice. J Leukoc Biol. 2005;78:114–21.CrossRefPubMed

16.

Jovicic N, Jeftic I, Jovanovic I, Radosavljevic G, Arsenijevic N, Lukic ML, Pejnovic N. Differential immunometabolic phenotype in Th1 and Th2 dominant mouse strains in response to high-fat feeding. PLoS ONE. 2015;10:e0134089.CrossRefPubMedPubMedCentral

17.

Wang TY, Chen KY, Jhan KY, Li CH, Jung SM, Wang LC. Temporal-spatial expressions of interleukin-4, interleukin-10, and interleukin-13 in the brains of C57BL/6 and BALB/c mice infected with Angiostrongylus cantonensis: an immunohistochemical study. J Microbiol Immunol Infect. 2020;53:592–603.CrossRefPubMed

18.

Chang PK, Yu L, Chen JC. Dopamine D3 receptor blockade rescues hyper-dopamine activity-induced deficit in novel object recognition memory. Neuropharmacology. 2018;133:216–23.CrossRefPubMed

19.

Jhan KY, Cheng CJ, Jung SM, Lai YJ, Chen KY, Wang LC. Co-therapy of albendazole and dexamethasone reduces pathological changes in the cerebral parenchyma of Th-1 and Th-2 dominant mice heavily infected with Angiostrongylus cantonensis: histopathological and RNA-seq analyses. Biomolecules. 2021;11:536.CrossRefPubMedPubMedCentral

20.

Frankfurt M, Luine V. The evolving role of dendritic spines and memory: interaction(s) with estradiol. Horm Behav. 2015;74:28–36.CrossRefPubMedPubMedCentral

21.

Mahmmoud RR, Sase S, Aher YD, Sase A, Gröger M, Mokhtar M, Höger H, Lubec G. Spatial and working memory is linked to spine density and mushroom Spines. PLoS ONE. 2015;10:e0139739.CrossRefPubMedPubMedCentral

22.

Delint-Ramírez I, Salcedo-Tello P, Bermudez-Rattoni F. Spatial memory formation induces recruitment of NMDA receptor and PSD-95 to synaptic lipid rafts. J Neurochem. 2008;106:1658–68.CrossRefPubMed

23.

Frick KM, Fernandez SM. Enrichment enhances spatial memory and increases synaptophysin levels in aged female mice. Neurobiol Aging. 2003;24:615–26.CrossRefPubMed

24.

Hamos JE, DeGennaro LJ, Drachman DA. Synaptic loss in Alzheimer’s disease and other dementias. Neurology. 1989;39:355–61.CrossRefPubMed

25.

Scheff SW, Price DA, Schmitt FA, Mufson EJ. Hippocampal synaptic loss in early Alzheimer’s disease and mild cognitive impairment. Neurobiol Aging. 2006;27:1372–84.CrossRefPubMed

26.

Subramanian J, Savage JC, Tremblay MÈ. Synaptic loss in Alzheimer’s Disease: echanistic Insights Provided by Two-Photon in vivo Imaging of Transgenic Mouse Models. Front Cell Neurosci. 2020;14:592607.CrossRefPubMedPubMedCentral

27.

Rao JS, Kellom M, Kim HW, Rapoport SI. Neuroinflammation and synaptic loss. Neurochem Res. 2012;37:903–10.CrossRefPubMedPubMedCentral

28.

Chen KY, Cheng CJ, Wang LC. Activation of sonic hedgehog leads to survival enhancement of astrocytes via the GRP78-dependent pathway in mice infected with Angiostrongylus cantonensis. Biomed Res Int. 2015;2015:674371.PubMedPubMedCentral

29.

Chen KY, Chiu CH, Wang LC. Anti-apoptotic effects of Sonic hedgehog signalling through oxidative stress reduction in astrocytes co-cultured with excretory-secretory products of larval Angiostrongylus cantonensis. Sci Rep. 2017;7:41574.CrossRefPubMedPubMedCentral

30.

Chen KY, Wang LC. Stimulation of IL-1β and IL-6 through NF-κB and sonic hedgehog-dependent pathways in mouse astrocytes by excretory/secretory products of fifth-stage larval Angiostrongylus cantonensis. Parasit Vectors. 2017;10:445.CrossRefPubMedPubMedCentral

31.

Chen KY, Cheng CJ, Cheng CC, Jhan KY, Chen YJ, Wang LC. The excretory/secretory products of fifth-stage larval Angiostrongylus cantonensis induces autophagy via the Sonic hedgehog pathway in mouse brain astrocytes. PLoS Negl Trop Dis. 2020;14:e0008290.CrossRefPubMedPubMedCentral

32.

Chen KY, Chen YJ, Cheng CJ, Jhan KY, Wang LC. Excretory/secretory products of Angiostrongylus cantonensis fifth-stage larvae induce endoplasmic reticulum stress via the Sonic hedgehog pathway in mouse astrocytes. Parasit Vectors. 2020;13:317.CrossRefPubMedPubMedCentral

33.

Gosnell WL, Kramer KJ. The role of eosinophils in angiostrongyliasis: multiple roles for a versatile cell? Hawaii J Med Public Health. 2013;72:49–51.PubMedPubMedCentral

34.

Gustafsson D, Klang A, Thams S, Rostami E. The role of BDNF in experimental and clinical traumatic brain injury. Int J Mol Sci. 2021;22:3582.CrossRefPubMedPubMedCentral

35.

Failla MD, Conley YP, Wagner AK. Brain-derived neurotrophic factor in traumatic brain injury-related mortality: interrelationships between genetics and acute systemic and central nervous system BDNF profiles. Neurorehabil Neural Repair. 2016;30:83–93.CrossRefPubMed

36.

Kipnis J, Cohen H, Cardon M, Ziv Y, Schwartz M. T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions. PNAS. 2004;101:8180–5.CrossRefPubMedPubMedCentral

37.

Derecki NC, Cardani AN, Yang CH, Quinnies KM, Crihfield A, Lynch K, Kipnis J. Regulation of learning and memory by meningeal immunity: a key role for IL-4. J Exp Med. 2009;207:1067–80.CrossRef

38.

Chen L, Pan H, Bai Y, Li H, Yang W, Lin ZX, Cui W, Xian YF. Gelsemine, a natural alkaloid extracted from Gelsemium elegans Benth alleviates neuroinflammation and cognitive impairments in Aβ oligomer-treated mice. Psychopharmacology. 2020;237:2111–24.CrossRefPubMed

Title: Synaptic loss and progression in mice infected with Angiostrongylus cantonensis in the early stage
Authors: Kai-Yuan Jhan
Pi-Kai Chang
Chien-Ju Cheng
Shih-Ming Jung
Lian-Chen Wang
Publication date: 01-12-2022
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2022
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-022-02436-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Synaptic loss and progression in mice infected with Angiostrongylus cantonensis in the early stage

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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