Skip to main content

Alteration in peritoneal cells with the chemokine CX3CL1 reverses age-associated impairment of recognition memory

Abstract

Cognitive function progressively declines with advancing age. The aging process can be promoted by obesity and attenuated by exercise. Both conditions affect levels of the chemokine CX3CL1 in peripheral tissues; however, its role in cognitive aging is unknown. In the current study, we administered CX3CL1 into the peritoneal cavity of aged mice to investigate its impact on the aging process. In the peritoneal cavity, CX3CL1 not only reversed the age-associated accumulation of cells expressing the senescence marker p16INK4a but also increased peritoneal phagocytic activity, indicating that CX3CL1 affected the phenotypes of peritoneal cells. In the hippocampus of aged mice, intraperitoneal administration of CX3CL1 increased the number of Type-2 neural stem cells and promoted brain-derived neurotrophic factor (BDNF) expression. This treatment, furthermore, improved novel object recognition memory impaired with advancing age. Intraperitoneal transplantation of peritoneal cells from CX3CL1-treated aged mice improved novel object recognition memory in recipient aged mice. It indicates that peritoneal cells have a critical role in the CX3CL1-induced improvement of recognition memory in aged mice. Vagotomy inhibited the CX3CL1-induced increase in BDNF expression, demonstrating that the vagus nerve is involved in the hippocampal BDNF expression induced by intraperitoneal administration of CX3CL1. Thus, our results demonstrate that a novel connection among the peritoneal cells, the vagus nerve, and the hippocampus can reverse the age-associated decline in recognition memory.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. Plancher G, Gyselinck V, Nicolas S, Piolino P. Age effect on components of episodic memory and feature binding: a virtual reality study. Neuropsychology. 2010;24(3):379–90.

    PubMed  Article  Google Scholar 

  2. Friedman D. The cognitive aging of episodic memory: a view based on the event-related brain potential. Front Behav Neurosci. 2013;7:111.

    PubMed  PubMed Central  Article  Google Scholar 

  3. Franz CE, et al. Body mass trajectories and cortical thickness in middle-aged men: a 42-year longitudinal study starting in young adulthood. Neurobiol Aging. 2019;79:11–21.

    PubMed  PubMed Central  Article  Google Scholar 

  4. Ronan L, et al. Obesity associated with increased brain age from midlife. Neurobiol Aging. 2016;47:63–70.

    PubMed  PubMed Central  Article  Google Scholar 

  5. Whitmer RA, Gunderson EP, Barrett-Connor E, Quesenberry CP, Yaffe K. Obesity in middle age and future risk of dementia: a 27 year longitudinal population based study. BMJ. 2005;330(7504):1360.

    PubMed  PubMed Central  Article  Google Scholar 

  6. Xu WL, Atti AR, Gatz M, Pedersen NL, Johansson B, Fratiglioni L. Midlife overweight and obesity increase late-life dementia risk: a population-based twin study. Neurology. 2011;76(18):1568–74.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. Busse AL, Gil G, Santarém JM, Jacob FW. Physical activity and cognition in the elderly: a review. Dement Neuropsychol. 2009;3:204–8.

    PubMed  PubMed Central  Article  Google Scholar 

  8. van Praag H, Shubert T, Zhao C, Gage FH. Exercise enhances learning and hippocampal neurogenesis in aged mice. J Neurosci. 2005;25(38):8680–5.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  9. Speisman RB, Kumar A, Rani A, Foster TC, Ormerod BK. Daily exercise improves memory, stimulates hippocampal neurogenesis and modulates immune and neuroimmune cytokines in aging rats. Brain Behav Immun. 2013;28:25–43.

    CAS  PubMed  Article  Google Scholar 

  10. Catoire M, Mensink M, Kalkhoven E, Schrauwen P, Kersten S. Identification of human exercise-induced myokines using secretome analysis. Physiol Genomics. 2014;46(7):256–67.

    CAS  PubMed  Article  Google Scholar 

  11. Strömberg A, Olsson K, Dijksterhuis JP, Rullman E, Schulte G, Gustafsson T. CX3CL1–a macrophage chemoattractant induced by a single bout of exercise in human skeletal muscle. Am J Physiol Regul Integr Comp Physiol. 2016;310(3):R297-304.

    PubMed  Article  Google Scholar 

  12. Lee S, et al. CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer’s disease mouse models. Am J Pathol. 2010;177(5):2549–62.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. Winter AN, et al. Two forms of CX3CL1 display differential activity and rescue cognitive deficits in CX3CL1 knockout mice. J Neuroinflammation. 2020;17(1):157.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. Shah R, et al. Fractalkine is a novel human adipochemokine associated with type 2 diabetes. Diabetes. 2011;60(5):1512–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. Ganguli M, et al. Aging, diabetes, obesity, and cognitive decline: a population-based study. J Am Geriatr Soc. 2020;68(5):991–8.

    PubMed  PubMed Central  Article  Google Scholar 

  16. Bazan JF, et al. A new class of membrane-bound chemokine with a CX3C motif. Nature. 1997;385(6617):640–4.

    CAS  PubMed  Article  Google Scholar 

  17. Hundhausen C, et al. The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell-cell adhesion. Blood. 2003;102(4):1186–95.

    CAS  PubMed  Article  Google Scholar 

  18. Garton KJ, et al. Tumor necrosis factor-alpha-converting enzyme (ADAM17) mediates the cleavage and shedding of fractalkine (CX3CL1). J Biol Chem. 2001;276(41):37993–8001.

    CAS  PubMed  Article  Google Scholar 

  19. Davies JQ, Gordon S. Isolation and culture of murine macrophages. Methods Mol Biol. 2005;290:91–103.

    PubMed  Google Scholar 

  20. Akkerman S, et al. Object recognition testing: methodological considerations on exploration and discrimination measures. Behav Brain Res. 2012;232(2):335–47.

    PubMed  Article  Google Scholar 

  21. Antunes M, Biala G. The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process. 2012;13(2):93–110.

    CAS  PubMed  Article  Google Scholar 

  22. Leger M, et al. Object recognition test in mice. Nat Protoc. 2013;8(12):2531–7.

    CAS  PubMed  Article  Google Scholar 

  23. Krishnamurthy J, et al. Ink4a/Arf expression is a biomarker of aging. J Clin Invest. 2004;114(9):1299–307.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. Linehan E, Dombrowski Y, Snoddy R, Fallon PG, Kissenpfennig A, Fitzgerald DC. Aging impairs peritoneal but not bone marrow-derived macrophage phagocytosis. Aging Cell. 2014;13(4):699–708.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. Hughes RN. The value of spontaneous alternation behavior (SAB) as a test of retention in pharmacological investigations of memory. Neurosci Biobehav Rev. 2004;28(5):497–505.

    CAS  PubMed  Article  Google Scholar 

  26. Kempermann G, Jessberger S, Steiner B, Kronenberg G. Milestones of neuronal development in the adult hippocampus. Trends Neurosci. 2004;27(8):447–52.

    CAS  PubMed  Article  Google Scholar 

  27. Brazel CY, et al. Sox2 expression defines a heterogeneous population of neurosphere-forming cells in the adult murine brain. Aging Cell. 2005;4:197–207.

    CAS  PubMed  Article  Google Scholar 

  28. Yu DX, Marchetto MC, Gage FH. How to make a hippocampal dentate gyrus granule neuron. Development. 2014;141(12):2366–75.

    CAS  PubMed  Article  Google Scholar 

  29. Uda Y, Xu S, Matsumura T, Takei Y. P2Y4 Nucleotide receptor in neuronal precursors induces glutamatergic subtype markers in their descendant neurons. Stem Cell Reports. 2016;6(4):474–82.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. Mah LJ, El-Osta A, Karagiannis TC. GammaH2AX as a molecular marker of aging and disease. Epigenetics. 2010;5(2):129–36.

    CAS  PubMed  Article  Google Scholar 

  31. Maynard S, Fang EF, Scheibye-Knudsen M, Croteau DL, Bohr VA. DNA damage, DNA repair, aging, and neurodegeneration. Cold Spring Harb Perspect Med. 2015;5(10)

  32. Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem. 1998;273(10):5858–68.

    CAS  PubMed  Article  Google Scholar 

  33. Riopel M, et al. Chronic fractalkine administration improves glucose tolerance and pancreatic endocrine function. J Clin Invest. 2018;128(4):1458–70.

    PubMed  PubMed Central  Article  Google Scholar 

  34. Liu PZ, Nusslock R. Exercise-mediated neurogenesis in the hippocampus via BDNF. Front Neurosci. 2018;12:52.

    PubMed  PubMed Central  Article  Google Scholar 

  35. Lee J, Duan W, Mattson MP. Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J Neurochem. 2002;82(6):1367–75.

    CAS  PubMed  Article  Google Scholar 

  36. Rossi C, et al. Brain-derived neurotrophic factor (BDNF) is required for the enhancement of hippocampal neurogenesis following environmental enrichment. Eur J Neurosci. 2006;24(7):1850–6.

    PubMed  Article  Google Scholar 

  37. Heldt SA, Stanek L, Chhatwal JP, Ressler KJ. Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories. Mol Psychiatry. 2007;12(7):656–70.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. Jessberger S, et al. Dentate gyrus-specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats. Learn Mem. 2009;16(2):147–54.

    PubMed  PubMed Central  Article  Google Scholar 

  39. Radiske A, Rossato JI, Gonzalez MC, Köhler CA, Bevilaqua LR, Cammarota M. BDNF controls object recognition memory reconsolidation. Neurobiol Learn Mem. 2017;142(Pt A):79–84.

    CAS  PubMed  Article  Google Scholar 

  40. Hattiangady B, Rao MS, Shetty GA, Shetty AK. Brain-derived neurotrophic factor, phosphorylated cyclic AMP response element binding protein and neuropeptide Y decline as early as middle age in the dentate gyrus and CA1 and CA3 subfields of the hippocampus. Exp Neurol. 2005;195(2):353–71.

    CAS  PubMed  Article  Google Scholar 

  41. Romine J, Gao X, Xu XM, So KF, Chen J. The proliferation of amplifying neural progenitor cells is impaired in the aging brain and restored by the mTOR pathway activation. Neurobiol Aging. 2015;36(4):1716–26.

    CAS  PubMed  Article  Google Scholar 

  42. Villeda SA, et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 2011;477(7362):90–4.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. Yang TT, et al. Aging and exercise affect hippocampal neurogenesis via different mechanisms. PLoS ONE. 2015;10(7): e0132152.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  44. Takei Y. Age-dependent decline in neurogenesis of the hippocampus and extracellular nucleotides. Hum Cell. 2019;32(2):88–94.

    CAS  PubMed  Article  Google Scholar 

  45. Nagashimada M, et al. CX3CL1-CX3CR1 signaling deficiency exacerbates obesity-induced inflammation and insulin resistance in male mice. Endocrinology. 2021;162(6):bqab064.

    PubMed  Article  Google Scholar 

  46. Prechtl JC, Powley TL. The fiber composition of the abdominal vagus of the rat. Anat Embryol (Berl). 1990;181(2):101–15.

    CAS  Article  Google Scholar 

  47. Bercik P, et al. The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication. Neurogastroenterol Motil. 2011;23(12):1132–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. Bercik P, et al. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology. 2011;141(2):599–609, 609.e1.

  49. O’Leary OF, et al. The vagus nerve modulates BDNF expression and neurogenesis in the hippocampus. Eur Neuropsychopharmacol. 2018;28(2):307–16.

    PubMed  Article  CAS  Google Scholar 

  50. Maqsood R, Stone TW. The gut-brain Axis, BDNF, NMDA and CNS disorders. Neurochem Res. 2016;41(11):2819–35.

    CAS  PubMed  Article  Google Scholar 

  51. Di Micco R, Krizhanovsky V, Baker D, Adda di Fagagna F. Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nat Rev Mol Cell Biol. 2021;22(2):75–95.

    PubMed  Article  CAS  Google Scholar 

  52. Hall BM, et al. p16(Ink4a) and senescence-associated β-galactosidase can be induced in macrophages as part of a reversible response to physiological stimuli. Aging (Albany NY). 2017;9(8):1867–84.

    CAS  Article  Google Scholar 

  53. Liu JY, et al. Cells exhibiting strong p16INK4a promoter activation in vivo display features of senescence. Proc Natl Acad Sci U S A. 2019;116(7):2603–11.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. de la Fuente M, Martin MI, Ortega E. Changes in the phagocytic function of peritoneal macrophages from old mice after strenuous physical exercise. Comp Immunol Microbiol Infect Dis. 1990;13(4):189–98.

    PubMed  Article  Google Scholar 

  55. Sugiura H, Nishida H, Inaba R, Mirbod SM, Iwata H. Effects of different durations of exercise on macrophage functions in mice. J Appl Physiol. 2001;90(3):789–94.

    CAS  PubMed  Article  Google Scholar 

Download references

Funding

This work was supported by JSPS Grant-in-Aid for Exploratory Research (Exploratory), Grant Number: 18K18454.

Author information

Authors and Affiliations

Authors

Contributions

Y.T. conceived and designed this study. Y.T., Y.A., K.I., S.T., T.T., and A.H. performed experiments. Y.T., T.T., and A.H. analyzed and interpreted data. A.G., R.K., A.M., H.I-N., S.K., and A.S. provided technical support and discussions. Y.T. and Y.A. wrote the manuscript. All authors reviewed the manuscript.

Corresponding author

Correspondence to Yoshinori Takei.

Ethics declarations

Ethics approval

All animal procedures were approved by the Animal Care and Use Committee of Kyoto University (No. 15–45-3) and the Animal Care and User Committee of Toho University (No. 21–53-430). Efforts were made to minimize animal suffering and to reduce the number of animals used.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

11357_2022_579_MOESM1_ESM.pdf

Supplementary file1 Comparison between amino acid sequences of human and mouse CX3CL1 chemokine domains. Amino acid sequence of the human CX3CL1 chemokine domain shows 78% identity and 86% similarity to that of mouse. Protein BLAST (National Center for Biotechnology Information) was used for the comparison. (PDF 93 KB)

11357_2022_579_MOESM2_ESM.pdf

Supplementary file2 Novel object recognition test for female aged CX3CL1 mice. CX3CL1 treatment, but not saline (vehicle), promoted preference for the novel object over a familiar object. Experimental procedures were as described in the main text. (*p < 0.05 vs. saline-treated mouse). Data represent the mean ± SEM; n = 3. (PDF 22 KB)

11357_2022_579_MOESM3_ESM.pdf

Supplementary file3 Fluorescence intensity of cells judged as positive. Fluorescence intensities of cells judged as positive in Fig 4a (a) and Fig 6a (b) were measured with the application Image J Ver. 2.1.0/1.53c (National Institute of Health). In (a), significant difference between samples derived from mice treated with either saline or CX3CL1 was not detected with a unpaired Student’s t-test. Data represent the mean ± SEM of randomly selected 30 positive cells from indicated samples. In (b), significant difference was detected with a non-repeated measures ANOVA test. The post-hoc Bonferroni correction indicated significant differences between samples from naïve mice and CX3CL1-treated mice, and between samples from naïve mice and CX3CL1-treated mice with sham operation. Data represent the mean ± SEM of randomly selected 30 positive cells from indicated samples. In the right, fluorescence intensities were indicated as a box and whisker plot to show their variation. (PDF 32 KB)

About this article

Verify currency and authenticity via CrossMark

Cite this article

Takei, Y., Amagase, Y., Iida, K. et al. Alteration in peritoneal cells with the chemokine CX3CL1 reverses age-associated impairment of recognition memory. GeroScience (2022). https://doi.org/10.1007/s11357-022-00579-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11357-022-00579-3

Keywords

  • Peritoneal cells
  • Novel object recognition
  • BDNF
  • Rejuvenation