Hippocampal β2‑microglobulin mediates sepsis‑induced cognitive impairment

Gao,Rong; Li,Guomin; Yang,Runhua; Yuan,Hongmei; Zhang,Shaogang

doi:10.3892/mmr.2018.8858

Hippocampal β2‑microglobulin mediates sepsis‑induced cognitive impairment

Authors:
- Rong Gao
- Guomin Li
- Runhua Yang
- Hongmei Yuan
- Shaogang Zhang
View Affiliations

Affiliations: Department of Emergency and Intensive Care Medicine, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Affiliated with Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210014, P.R. China, Department of Anesthesiology and Intensive Care, Jintan Hospital, Jiangsu University, Jintan, Changzhou 213200, P.R. China, Department of Anesthesiology, Nanjing Maternity and Child Health Care Hospital, Nanjing Medical University, Nanjing, Jiangsu 210004, P.R. China, Department of Anesthesiology, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Affiliated with Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210014, P.R. China
Published online on: April 5, 2018 https://doi.org/10.3892/mmr.2018.8858
Pages: 7813-7820

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Acute brain dysfunction is a frequent complication in sepsis patients and is associated with long‑term neurocognitive consequences and increased mortality, yet the underlying mechanism remains unclear. Emerging evidence has suggested that β2‑microglobulin [a component of major histocompatibility complex (MHC) class I molecules] is involved in cognitive dysfunction in various neurological diseases. Therefore, the present study tested the hypothesis that β2‑microglobulin in the brain also mediates sepsis‑induced cognitive impairment. In the present study, wild‑type and antigen processing 1 (Tap1)‑deficient mice (Tap1‑/‑) were subjected to cecal ligation and puncture (CLP). Survival rate, cognitive function, and biochemical analysis were performed at the indicated time points. The data revealed that CLP induced anxiety‑like behavior and impaired hippocampal‑dependent contextual memory in wild‑type mice, which was accompanied by hippocampal microglial activation, increased level of interleukin‑1β, and decreased concentrations of brain derived neurotrophic factor and postsynaptic density protein 95. Notably, it was demonstrated that Tap1‑/‑ mice with reduced cell surface expression of MHC I protected mice from anxiety‑like behavior and impaired hippocampal‑dependent contextual memory and reversed most of these biochemical parameters following sepsis development. In summary, the results of the present study suggest that β2‑microglobulin negatively regulates cognitive impairment in an animal model of sepsis induced by CLP.

View Figures

View References

1	Widmann CN and Heneka MT: Long-term cerebral consequences of sepsis. Lancet Neurol. 13:630–636. 2014. View Article : Google Scholar : PubMed/NCBI
2	Gofton TE and Young GB: Sepsis-associated encephalopathy. Nat Rev Neurol. 8:557–566. 2012. View Article : Google Scholar : PubMed/NCBI
3	Iwashyna TJ, Ely EW, Smith DM and Langa KM: Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA. 304:1787–1794. 2010. View Article : Google Scholar : PubMed/NCBI
4	Gao R, Kan MQ, Wang SG, Yang RH and Zhang SG: Disrupted tryptophan metabolism induced cognitive impairment in a mouse model of sepsis-associated encephalopathy. Inflammation. 39:550–560. 2016. View Article : Google Scholar : PubMed/NCBI
5	Koh ES, Lee K, Kim SH, Kim YO, Jin DC, Song HC, Choi EJ, Kim YL, Kim YS, Kang SW, et al: Serum β2-microglobulin predicts mortality in peritoneal dialysis patients: A prospective cohort study. Am J Nephrol. 42:91–98. 2015. View Article : Google Scholar : PubMed/NCBI
6	Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, Fainberg N, Ding Z, Eggel A, et al: The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 477:90–94. 2011. View Article : Google Scholar : PubMed/NCBI
7	Smith LK, He Y, Park JS, Bieri G, Snethlage CE, Lin K, Gontier G, Wabl R, Plambeck KE, Udeochu J, et al: β2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis. Nat Med. 21:932–937. 2015. View Article : Google Scholar : PubMed/NCBI
8	Murray AM: Cognitive impairment in the aging dialysis and chronic kidney disease populations: An occult burden. Adv Chronic Kidney Dis. 15:123–132. 2008. View Article : Google Scholar : PubMed/NCBI
9	Glynn MW, Elmer BM, Garay PA, Liu XB, Needleman LA, El-Sabeawy F and McAllister AK: MHCI negatively regulates synapse density during the establishment of cortical connections. Nat Neurosci. 14:442–451. 2011. View Article : Google Scholar : PubMed/NCBI
10	Elmer BM and McAllister AK: Major histocompatibility complex class I proteins in brain development and plasticity. Trends Neurosci. 35:660–670. 2012. View Article : Google Scholar : PubMed/NCBI
11	Carrette O, Demalte I, Scherl A, Yalkinoglu O, Corthals G, Burkhard P, Hochstrasser DF and Sanchez JC: A panel of cerebrospinal fluid potential biomarkers for the diagnosis of Alzheimer's disease. Proteomics. 3:1486–1494. 2003. View Article : Google Scholar : PubMed/NCBI
12	McArthur JC, Nance-Sproson TE, Griffin DE, Hoover D, Selnes OA, Miller EN, Margolick JB, Cohen BA, Farzadegan H and Saah A: The diagnostic utility of elevation in cerebrospinal fluid beta 2-microglobulin in HIV-1 dementia. Multicenter AIDS cohort study. Neurology. 42:1707–1712. 1992. View Article : Google Scholar : PubMed/NCBI
13	Gao R, Ji MH, Gao DP, Yang RH, Zhang SG, Yang JJ and Shen JC: Neuroinflammation-induced downregulation of hippocampacal neuregulin 1-ErbB4 signaling in the parvalbumin interneurons might contribute to cognitive impairment in a mouse model of sepsis-associated encephalopathy. Inflammation. 40:387–400. 2017. View Article : Google Scholar : PubMed/NCBI
14	Gao R, Tang YH, Tong JH, Yang JJ, Ji MH and Zhu SH: Systemic lipopolysaccharide administration-induced cognitive impairments are reversed by erythropoietin treatment in mice. Inflammation. 38:1949–1958. 2015. View Article : Google Scholar : PubMed/NCBI
15	Melani R, Chelini G, Cenni MC and Berardi N: Enriched environment effects on remote object recognition memory. Neuroscience. 352:296–305. 2017. View Article : Google Scholar : PubMed/NCBI
16	Ji MH, Qiu LL, Tang H, Ju LS, Sun XR, Zhang H, Jia M, Zuo ZY, Shen JC and Yang JJ: Sepsis-induced selective parvalbumin interneuron phenotype loss and cognitive impairments may be mediated by NADPH oxidase 2 activation in mice. J Neuroinflammation. 12:1822015. View Article : Google Scholar : PubMed/NCBI
17	Wu J, Dong L, Zhang M, Jia M, Zhang G, Qiu L, Ji M and Yang J: Class I histone deacetylase inhibitor valproic acid reverses cognitive deficits in a mouse model of septic encephalopathy. Neurochem Res. 38:2440–2449. 2013. View Article : Google Scholar : PubMed/NCBI
18	Schramm P, Klein KU, Falkenberg L, Berres M, Closhen D, Werhahn KJ, David M, Werner C and Engelhard K: Impaired cerebrovascular autoregulation in patients with severe sepsis and sepsis-associated delirium. Crit Care. 16:R1812012. View Article : Google Scholar : PubMed/NCBI
19	Fang J, Lian Y, Xie K, Cai S and Wen P: Epigenetic modulation of neuronal apoptosis and cognitive functions in sepsis-associated encephalopathy. Neurol Sci. 35:283–288. 2014. View Article : Google Scholar : PubMed/NCBI
20	Berg RM, Møller K and Bailey DM: Neuro-oxidative-nitrosative stress in sepsis. J Cereb Blood Flow Metab. 31:1532–1544. 2011. View Article : Google Scholar : PubMed/NCBI
21	Okuno S, Ishimura E, Kohno K, Fujino-Katoh Y, Maeno Y, Yamakawa T, Inaba M and Nishizawa Y: Serum beta2-microglobulin level is a significant predictor of mortality in maintenance haemodialysis patients. Nephrol Dial Transplant. 24:571–577. 2009. View Article : Google Scholar : PubMed/NCBI
22	Wu HC, Lee LC and Wang WJ: Associations among serum Beta 2 microglobulin, malnutrition, inflammation, and advanced cardiovascular event in patients with chronic kidney disease. J Clin Lab Anal. 31–May;2017.doi: 10.1002/jcla.22056. View Article : Google Scholar
23	Raikou VD and Kyriaki D: The relationship between glycemic control, beta2-microglobulin and inflammation in patients on maintenance dialysis treatment. J Diabetes Metab Disord. 14:342015. View Article : Google Scholar : PubMed/NCBI
24	Imamura Y, Wang H, Matsumoto N, Muroya T, Shimazaki J, Ogura H and Shimazu T: Interleukin-1β causes long-term potentiation deficiency in a mouse model of septic encephalopathy. Neuroscience. 187:63–69. 2011. View Article : Google Scholar : PubMed/NCBI
25	Hoshino K, Hayakawa M and Morimoto Y: Minocycline prevents the impairment of hippocampal long-term potentiation in the septic mouse. Shock. 48:209–214. 2017. View Article : Google Scholar : PubMed/NCBI
26	Snigdha S, Prieto GA, Petrosyan A, Loertscher BM, Dieskau AP, Overman LE and Cotman CW: H3K9me3 inhibition improves memory, promotes spine formation, and increases BDNF levels in the aged hippocampus. J Neurosci. 36:3611–3622. 2016. View Article : Google Scholar : PubMed/NCBI
27	Yu H, Liao Y, Li T, Cui Y, Wang G, Zhao F and Jin Y: Alterations of synaptic proteins in the hippocampus of mouse offspring induced by developmental lead exposure. Mol Neurobiol. 53:6786–6798. 2016. View Article : Google Scholar : PubMed/NCBI
28	Zhu D, Li C, Swanson AM, Villalba RM, Guo J, Zhang Z, Matheny S, Murakami T, Stephenson JR, Daniel S, et al: BAI1 regulates spatial learning and synaptic plasticity in the hippocampus. J Clin Invest. 125:1497–1508. 2015. View Article : Google Scholar : PubMed/NCBI
29	Chao HW, Tsai LY, Lu YL, Lin PY, Huang WH, Chou HJ, Lu WH, Lin HC, Lee PT and Huang YS: Deletion of CPEB3 enhances hippocampus-dependent memory via increasing expressions of PSD95 and NMDA receptors. J Neurosci. 33:17008–17022. 2013. View Article : Google Scholar : PubMed/NCBI
30	Kim DM and Leem YH: Chronic stress-induced memory deficits are reversed by regular exercise via AMPK-mediated BDNF induction. Neuroscience. 324:271–285. 2016. View Article : Google Scholar : PubMed/NCBI
31	Kim E and Sheng M: PDZ domain proteins of synapses. Nat Rev Neurosci. 5:771–781. 2004. View Article : Google Scholar : PubMed/NCBI
32	Şahin TD, Karson A, Balcı F, Yazır Y, Bayramgürler D and Utkan T: TNF-alpha inhibition prevents cognitive decline and maintains hippocampal BDNF levels in the unpredictable chronic mild stress rat model of depression. Behav Brain Res. 292:233–240. 2015. View Article : Google Scholar : PubMed/NCBI