Abstract
Neuroinflammation plays an early and prominent role in the pathology of Alzheimer’s disease (AD). Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) has been identified as a negative regulator of innate and adaptive immunity. However, whether TIPE2 affects cognitive functions in AD-like mouse models remains unknown. In this study, we compared the gene and protein expressions of TIPE2 between the APP/PS1 mice and the age-matched wild type (WT) mice at different stages of development using western blot and RT-qPCR. The hippocampal expression of the TIPE2 mRNA and protein in APP/PS1 mice was higher than that of the WT mice starting from 6 months to 10 months. However, the difference of the TIPE2 expression between the APP/PS1 mice and the WT mice declined in a time-dependent manner. The spatial learning and memory deficit from the 8-month-old APP/PS1 mice was observed in the Y-maze test and fear conditioning task. Interestingly, overexpression of TIPE2 by intra-hippocampal injection of AAV-TIPE2 into APP/PS1 mice resulted in an improvement of learning and memory and reduced expression of inflammatory cytokines, such as TNF-α, IL-6 and IL-1β, and increased expression of anti-inflammatory cytokines, such as IL-10 and Arg-1. Taken together, our findings show that the TIPE2 expression level was negatively correlated with the pathogenesis of Alzheimer’s disease, and overexpression of TIPE2 attenuates cognitive deficits in APP/PS1 mice, suggesting TIPE2 is a potential target for pharmacological intervention and improvement of cognitive deficits.
.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data Availability
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Abbreviations
- AD:
-
Alzheimer’s disease
- TIPE2:
-
Tumor necrosis factor-α-induced protein 8-like 2
- Aβ:
-
β-amyloid
- Iba1:
-
ionized calcium binding adaptor molecule 1
References
Bradshaw EM, Chibnik LB, Keenan BT, Ottoboni L, Raj T, Tang A, Rosenkrantz LL, Imboywa S, Lee M, Von Korff A, Alzheimer Disease Neuroimaging I, Morris MC, Evans DA, Johnson K, Sperling RA, Schneider JA, Bennett DA, De Jager PL (2013) CD33 Alzheimer's disease locus: altered monocyte function and amyloid biology. Nat Neurosci 16:848–850
Colonna M, Butovsky O (2017) Microglia function in the central nervous system during health and neurodegeneration. Annu Rev Immunol 35:441–468
Colton CA, Mott RT, Sharpe H, Xu Q, Van Nostrand WE, Vitek MP (2006) Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD. J Neuroinflammation 3:27
Crehan H, Hardy J, Pocock J (2013) Blockage of CR1 prevents activation of rodent microglia. Neurobiol Dis 54:139–149
Dai JX, Han HL, Tian M, Cao J, Xiu JB, Song NN, Huang Y, Xu TL, Ding YQ, Xu L (2008) Enhanced contextual fear memory in central serotonin-deficient mice. Proc Natl Acad Sci U S A 105:11981–11986
Freire D, Reyes RE, Baghram A, Davies DL, Asatryan L (2018) P2X7 receptor antagonist A804598 inhibits inflammation in brain and liver in C57BL/6J mice exposed to chronic ethanol and high fat diet. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology
Graeber MB (2010) Changing face of microglia. Science 330:783–788
Griciuc A, Serrano-Pozo A, Parrado AR, Lesinski AN, Asselin CN, Mullin K, Hooli B, Choi SH, Hyman BT, Tanzi RE (2013) Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 78:631–643
Guerreiro R et al (2013) TREM2 variants in Alzheimer's disease. N Engl J Med 368:117–127
Heneka MT et al (2015) Neuroinflammation in Alzheimer's disease. Lancet Neurol 14:388–405
Jay TR, Miller CM, Cheng PJ, Graham LC, Bemiller S, Broihier ML, Xu G, Margevicius D, Karlo JC, Sousa GL, Cotleur AC, Butovsky O, Bekris L, Staugaitis SM, Leverenz JB, Pimplikar SW, Landreth GE, Howell GR, Ransohoff RM, Lamb BT (2015) TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models. J Exp Med 212:287–295
Kaur C, Rathnasamy G, Ling EA (2017) Biology of microglia in the developing brain. J Neuropathol Exp Neurol 76:736–753
Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25:677–686
Masters CL, Bateman R, Blennow K, Rowe CC, Sperling RA, Cummings JL (2015) Alzheimer’s disease. Nat Rev Dis Primers 1:15056
Navarro V, Sanchez-Mejias E, Jimenez S, Munoz-Castro C, Sanchez-Varo R, Davila JC, Vizuete M, Gutierrez A, Vitorica J (2018) Microglia in Alzheimer's Disease: activated, dysfunctional or degenerative. Front Aging Neurosci 10:140
Ossenkoppele R et al (2015) The behavioural/dysexecutive variant of Alzheimer’s disease: clinical, neuroimaging and pathological features. Brain 138:2732–2749
Park J, Wetzel I, Marriott I, Dreau D, D'Avanzo C, Kim DY, Tanzi RE, Cho H (2018) A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer's disease. Nat Neurosci 21:941–951
Pimenova AA, Raj T, Goate AM (2018) Untangling genetic risk for Alzheimer's Disease. Biol Psychiatry 83:300–310
Pozueta J, Lefort R, Shelanski ML (2013) Synaptic changes in Alzheimer's disease and its models. Neuroscience 251:51–65
Shi Y, Holtzman DM (2018) Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight. Nat Rev Immunol 18:759–772
Shoham S, Linial M, Weinstock M (2018) Age-induced spatial memory deficits in rats are correlated with specific brain region alterations in microglial morphology and gene expression. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology
Sierra-Filardi EP-KA, Blanco FJ et al (2011) Activin a skews macrophage polarization by promoting a proinfl ammatory phenotype and inhibiting the acquisition of anti-infl ammatory macrophage markers. Blood 117:5092–5101
Spangenberg EE, Green KN (2017) Inflammation in Alzheimer's disease: lessons learned from microglia-depletion models. Brain Behav Immun 61:1–11
Sun H, Gong S, Carmody RJ, Hilliard A, Li L, Sun J, Kong L, Xu L, Hilliard B, Hu S, Shen H, Yang X, Chen YH (2008) TIPE2, a negative regulator of innate and adaptive immunity that maintains immune homeostasis. Cell 133:415–426
Suryavanshi PS, Ugale RR, Yilmazer-Hanke D, Stairs DJ, Dravid SM (2014) GluN2C/GluN2D subunit-selective NMDA receptor potentiator CIQ reverses MK-801-induced impairment in prepulse inhibition and working memory in Y-maze test in mice. Br J Pharmacol 171:799–809
Van Eldik LJ, Carrillo MC, Cole PE, Feuerbach D, Greenberg BD, Hendrix JA, Kennedy M, Kozauer N, Margolin RA, Molinuevo JL, Mueller R, Ransohoff RM, Wilcock DM, Bain L, Bales K (2016) The roles of inflammation and immune mechanisms in Alzheimer's disease. Alzheimers Dement 2:99–109
Zhang F, Jiang L (2015) Neuroinflammation in Alzheime’s disease. Neuropsychiatr Dis Treat:243
Zhang W, Rosenkranz JA (2013) Repeated restraint stress enhances cue-elicited conditioned freezing and impairs acquisition of extinction in an age-dependent manner. Behav Brain Res 248:12–24
Zhang G, Hao C, Lou Y, Xi W, Wang X, Wang Y, Qu Z, Guo C, Chen Y, Zhang Y, Liu S (2010) Tissue-specific expression of TIPE2 provides insights into its function. Mol Immunol 47:2435–2442
Zhang Y, Wei X, Liu L, Liu S, Wang Z, Zhang B, Fan B, Yang F, Huang S, Jiang F, Chen YH, Yi F (2012) TIPE2, a novel regulator of immunity, protects against experimental stroke. J Biol Chem 287:32546–32555
Zhang H, Zhu T, Liu W, Qu X, Chen Y, Ren P, Wang Z, Wei X, Zhang Y, Yi F (2015) TIPE2 acts as a negative regulator linking NOD2 and inflammatory responses in myocardial ischemia/reperfusion injury. J Mol Med 93:1033–1043
Acknowledgements
This work was supported by the research fundings granted to Fang ZHANG from the Natural Science Foundation of Shandong Province of China, No. ZR2016 HM 46; Post doctoral application foundation of Qingdao Municipal Bureau of Social Sciences, No. 2016062; Qingdao Science and Technology Bureau, No. 18-6-1-75-nsh; Clinical medicine +X Project of Qingdao University Medical Department, No. 2017 M08; and Innovation and Entrepreneurship Training Program of undergraduate student in Qingdao University, No. 201711065152.
Author information
Authors and Affiliations
Contributions
Fang Zhang, Wenjian Shao, Zhihong Yang, Lei Wang and Chuanxia Ju contributed to the experimental design. Yongzhen Miao, Zihan Xu and Ruoyu Zhang contributed to the experimental process. Yongzhen Miao wrote this article. Naidong Wang provided fund support for our supplementary experiment and revised our manuscript.
Corresponding author
Ethics declarations
Ethics Approval
The experiments were approved by the Qingdao University Experimental Animal Care and Use Committee.
Competing Interests
The authors declare that they have no competing interests.
Informed Consent
Not applicable.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Miao, Y., Wang, N., Shao, W. et al. Overexpression of TIPE2, a Negative Regulator of Innate and Adaptive Immunity, Attenuates Cognitive Deficits in APP/PS1 Mice. J Neuroimmune Pharmacol 14, 519–529 (2019). https://doi.org/10.1007/s11481-019-09861-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11481-019-09861-2