Skip to main content
Top
Published in: Translational Neurodegeneration 1/2019

Open Access 01-12-2019 | Alzheimer's Disease | Research

Transplantation of bone marrow derived macrophages reduces markers of neuropathology in an APP/PS1 mouse model

Authors: Luís Costa-Marques, Katrin Arnold, Marie-Christine Pardon, Christiane Leovsky, Samantha Swarbrick, Claire Fabian, Alexandra Stolzing

Published in: Translational Neurodegeneration | Issue 1/2019

Login to get access

Abstract

Background

We investigated early hallmarks of putative therapeutic effects following systemic transplantation of bone marrow derived macrophages (BM-M) in APP/PS1 transgenic mice.

Method

BM-M were transplanted into the tail vein and the animals analysed 1 month later.

Results

BM-M transplantation promoted the reduction of the amyloid beta [37-42] plaque number and size in the cortex and hippocampus of the treated mice, but no change in the more heavily modified pyroglutamate amyloid beta E3 plaques. The number of phenotypically ‘small’ microglia increased in the hippocampus. Astrocyte size decreased overall, indicating a reduction of activated astrocytes. Gene expression of interleukin 6 and 10, interferon-gamma, and prostaglandin E receptor 2 was significantly lower in the hippocampus, while interleukin 10 expression was elevated in the cortex of the treated mice.

Conclusions

BM-M systemically transplanted, promote a decrease in neuroinflammation and a limited reversion of amyloid pathology. This exploratory study may support the potential of BM-M or microglia-like cell therapy and further illuminates the mechanisms of action associated with such transplants.
Literature
1.
go back to reference Zhao R, Hu W, Tsai J, Li W, Gan W-B. Microglia limit the expansion of β-amyloid plaques in a mouse model of Alzheimer’s disease. Mol Neurodegener. 2017;12:47.CrossRef Zhao R, Hu W, Tsai J, Li W, Gan W-B. Microglia limit the expansion of β-amyloid plaques in a mouse model of Alzheimer’s disease. Mol Neurodegener. 2017;12:47.CrossRef
2.
go back to reference Lai AY, McLaurin J. Clearance of amyloid-β peptides by microglia and macrophages: the issue of what, when and where. Future Neurol. 2012;7(2):165–76.CrossRef Lai AY, McLaurin J. Clearance of amyloid-β peptides by microglia and macrophages: the issue of what, when and where. Future Neurol. 2012;7(2):165–76.CrossRef
3.
go back to reference Serrano-Pozo A, Gómez-Isla T, Growdon JH, Frosch MP, Hyman BT. A phenotypic change but not proliferation underlies glial responses in Alzheimer disease. Am J Pathol. 2013;182(6):2332–44.CrossRef Serrano-Pozo A, Gómez-Isla T, Growdon JH, Frosch MP, Hyman BT. A phenotypic change but not proliferation underlies glial responses in Alzheimer disease. Am J Pathol. 2013;182(6):2332–44.CrossRef
4.
go back to reference Mills CD. M1 and M2 macrophages: oracles of health and disease. Crit Rev Immunol. 2012;32(6):463–88.CrossRef Mills CD. M1 and M2 macrophages: oracles of health and disease. Crit Rev Immunol. 2012;32(6):463–88.CrossRef
5.
go back to reference Swirski FK, Hilgendorf I, Robbins CS. From proliferation to proliferation: monocyte lineage comes full circle. Semin Immunopathol. 2014;36(2):137–48.CrossRef Swirski FK, Hilgendorf I, Robbins CS. From proliferation to proliferation: monocyte lineage comes full circle. Semin Immunopathol. 2014;36(2):137–48.CrossRef
6.
go back to reference Hamelin L, Lagarde J, Dorothee G, Leroy C, Labit M, Comley RA, de Souza LC, Corne H, Dauphinot L, Bertoux M, et al. Early and protective microglial activation in Alzheimer’s disease: a prospective study using 18F-DPA-714 PET imaging. Brain. 2016;139(Pt 4):1252–64.CrossRef Hamelin L, Lagarde J, Dorothee G, Leroy C, Labit M, Comley RA, de Souza LC, Corne H, Dauphinot L, Bertoux M, et al. Early and protective microglial activation in Alzheimer’s disease: a prospective study using 18F-DPA-714 PET imaging. Brain. 2016;139(Pt 4):1252–64.CrossRef
7.
go back to reference Stolzing A, Sethe S, Grune T. Chronically active: activation of microglial proteolysis in ageing and neurodegeneration. Redox Rep. 2005;10(4):207–13.CrossRef Stolzing A, Sethe S, Grune T. Chronically active: activation of microglial proteolysis in ageing and neurodegeneration. Redox Rep. 2005;10(4):207–13.CrossRef
8.
go back to reference Krabbe G, Halle A, Matyash V, Rinnenthal JL, Eom GD, Bernhardt U, Miller KR, Prokop S, Kettenmann H, Heppner FL. Functional impairment of microglia coincides with Beta-amyloid deposition in mice with Alzheimer-like pathology. PLoS One. 2013;8(4):e60921.CrossRef Krabbe G, Halle A, Matyash V, Rinnenthal JL, Eom GD, Bernhardt U, Miller KR, Prokop S, Kettenmann H, Heppner FL. Functional impairment of microglia coincides with Beta-amyloid deposition in mice with Alzheimer-like pathology. PLoS One. 2013;8(4):e60921.CrossRef
9.
go back to reference Mosher KI, Wyss-Coray T. Microglial dysfunction in brain aging and Alzheimer’s disease. Biochem Pharmacol. 2014;88(4):594–604.CrossRef Mosher KI, Wyss-Coray T. Microglial dysfunction in brain aging and Alzheimer’s disease. Biochem Pharmacol. 2014;88(4):594–604.CrossRef
10.
go back to reference Takata K, Kitamura Y, Yanagisawa D, Morikawa S, Morita M, Inubushi T, Tsuchiya D, Chishiro S, Saeki M, Taniguchi T, et al. Microglial transplantation increases amyloid-beta clearance in Alzheimer model rats. FEBS Lett. 2007;581(3):475–8.CrossRef Takata K, Kitamura Y, Yanagisawa D, Morikawa S, Morita M, Inubushi T, Tsuchiya D, Chishiro S, Saeki M, Taniguchi T, et al. Microglial transplantation increases amyloid-beta clearance in Alzheimer model rats. FEBS Lett. 2007;581(3):475–8.CrossRef
11.
go back to reference Hohsfield LA, Humpel C. Intravenous infusion of monocytes isolated from 2-week-old mice enhances clearance of Beta-amyloid plaques in an Alzheimer mouse model. PLoS One. 2015;10(4):e0121930.CrossRef Hohsfield LA, Humpel C. Intravenous infusion of monocytes isolated from 2-week-old mice enhances clearance of Beta-amyloid plaques in an Alzheimer mouse model. PLoS One. 2015;10(4):e0121930.CrossRef
12.
go back to reference Zhu D, Yang N, Liu YY, Zheng J, Ji C, Zuo PP. M2 macrophage transplantation ameliorates cognitive dysfunction in amyloid-beta-treated rats through regulation of microglial polarization. J Alzheimers Dis. 2016;52(2):483–95.CrossRef Zhu D, Yang N, Liu YY, Zheng J, Ji C, Zuo PP. M2 macrophage transplantation ameliorates cognitive dysfunction in amyloid-beta-treated rats through regulation of microglial polarization. J Alzheimers Dis. 2016;52(2):483–95.CrossRef
13.
go back to reference Leovsky C, Fabian C, Naaldijk Y, Jager C, Jang HJ, Bohme J, Rudolph L, Stolzing A. Biodistribution of in vitro-derived microglia applied intranasally and intravenously to mice: effects of aging. Cytotherapy. 2015;17(11):1617–26.CrossRef Leovsky C, Fabian C, Naaldijk Y, Jager C, Jang HJ, Bohme J, Rudolph L, Stolzing A. Biodistribution of in vitro-derived microglia applied intranasally and intravenously to mice: effects of aging. Cytotherapy. 2015;17(11):1617–26.CrossRef
14.
go back to reference Moreno-Gonzalez I, Edwards Iii G, Salvadores N, Shahnawaz M, Diaz-Espinoza R, Soto C. Molecular interaction between type 2 diabetes and Alzheimer's disease through cross-seeding of protein misfolding. Mol Psychiatry. 2017;22(9):1327–34.CrossRef Moreno-Gonzalez I, Edwards Iii G, Salvadores N, Shahnawaz M, Diaz-Espinoza R, Soto C. Molecular interaction between type 2 diabetes and Alzheimer's disease through cross-seeding of protein misfolding. Mol Psychiatry. 2017;22(9):1327–34.CrossRef
15.
go back to reference Chey S, Claus C, Liebert UG. Improved method for simultaneous isolation of proteins and nucleic acids. Anal Biochem. 2011;411(1):164–6.CrossRef Chey S, Claus C, Liebert UG. Improved method for simultaneous isolation of proteins and nucleic acids. Anal Biochem. 2011;411(1):164–6.CrossRef
16.
go back to reference Wirths O, Breyhan H, Cynis H, Schilling S, Demuth H-U, Bayer TA. Intraneuronal pyroglutamate-Abeta 3–42 triggers neurodegeneration and lethal neurological deficits in a transgenic mouse model. Acta Neuropathol. 2009;118(4):487–96.CrossRef Wirths O, Breyhan H, Cynis H, Schilling S, Demuth H-U, Bayer TA. Intraneuronal pyroglutamate-Abeta 3–42 triggers neurodegeneration and lethal neurological deficits in a transgenic mouse model. Acta Neuropathol. 2009;118(4):487–96.CrossRef
17.
go back to reference Radde R, Bolmont T, Kaeser SA, Coomaraswamy J, Lindau D, Stoltze L, Calhoun ME, Jaggi F, Wolburg H, Gengler S, et al. Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep. 2006;7(9):940–6.CrossRef Radde R, Bolmont T, Kaeser SA, Coomaraswamy J, Lindau D, Stoltze L, Calhoun ME, Jaggi F, Wolburg H, Gengler S, et al. Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep. 2006;7(9):940–6.CrossRef
18.
go back to reference Sullivan CP, Berg EA, Elliott-Bryant R, Fishman JB, McKee AC, Morin PJ, Shia MA, Fine RE. Pyroglutamate-Aβ 3 and 11 colocalize in amyloid plaques in Alzheimer's disease cerebral cortex with pyroglutamate-Aβ 11 forming the central core. Neurosci Lett. 2011;505(2):109–12.CrossRef Sullivan CP, Berg EA, Elliott-Bryant R, Fishman JB, McKee AC, Morin PJ, Shia MA, Fine RE. Pyroglutamate-Aβ 3 and 11 colocalize in amyloid plaques in Alzheimer's disease cerebral cortex with pyroglutamate-Aβ 11 forming the central core. Neurosci Lett. 2011;505(2):109–12.CrossRef
19.
go back to reference Osborn LM, Kamphuis W, Wadman WJ, Hol EM. Astrogliosis: an integral player in the pathogenesis of Alzheimer's disease. Prog Neurobiol. 2016;144(Supplement C):121–41.CrossRef Osborn LM, Kamphuis W, Wadman WJ, Hol EM. Astrogliosis: an integral player in the pathogenesis of Alzheimer's disease. Prog Neurobiol. 2016;144(Supplement C):121–41.CrossRef
20.
go back to reference Hinze A, Stolzing A. Differentiation of mouse bone marrow derived stem cells toward microglia-like cells. BMC Cell Biol. 2011;12:35.CrossRef Hinze A, Stolzing A. Differentiation of mouse bone marrow derived stem cells toward microglia-like cells. BMC Cell Biol. 2011;12:35.CrossRef
21.
go back to reference Melief J, Koning N, Schuurman KG, Van De Garde MD, Smolders J, Hoek RM, Van Eijk M, Hamann J, Huitinga I. Phenotyping primary human microglia: tight regulation of LPS responsiveness. Glia. 2012;60(10):1506–17.CrossRef Melief J, Koning N, Schuurman KG, Van De Garde MD, Smolders J, Hoek RM, Van Eijk M, Hamann J, Huitinga I. Phenotyping primary human microglia: tight regulation of LPS responsiveness. Glia. 2012;60(10):1506–17.CrossRef
22.
go back to reference Condello C, Schain A, Grutzendler J. Multicolor time-stamp reveals the dynamics and toxicity of amyloid deposition. Sci Rep. 2011;1:19.CrossRef Condello C, Schain A, Grutzendler J. Multicolor time-stamp reveals the dynamics and toxicity of amyloid deposition. Sci Rep. 2011;1:19.CrossRef
23.
go back to reference Wang A, Das P, Switzer RC 3rd, Golde TE, Jankowsky JL. Robust amyloid clearance in a mouse model of Alzheimer's disease provides novel insights into the mechanism of amyloid-beta immunotherapy. J Neurosci. 2011;31(11):4124–36.CrossRef Wang A, Das P, Switzer RC 3rd, Golde TE, Jankowsky JL. Robust amyloid clearance in a mouse model of Alzheimer's disease provides novel insights into the mechanism of amyloid-beta immunotherapy. J Neurosci. 2011;31(11):4124–36.CrossRef
24.
go back to reference D'Arrigo C, Tabaton M, Perico A. N-terminal truncated pyroglutamyl beta amyloid peptide Abetapy3-42 shows a faster aggregation kinetics than the full-length Abeta1-42. Biopolymers. 2009;91(10):861–73.CrossRef D'Arrigo C, Tabaton M, Perico A. N-terminal truncated pyroglutamyl beta amyloid peptide Abetapy3-42 shows a faster aggregation kinetics than the full-length Abeta1-42. Biopolymers. 2009;91(10):861–73.CrossRef
25.
go back to reference De Kimpe L, van Haastert ES, Kaminari A, Zwart R, Rutjes H, Hoozemans JJM, Scheper W. Intracellular accumulation of aggregated pyroglutamate amyloid beta: convergence of aging and Aβ pathology at the lysosome. Age. 2013;35(3):673–87.CrossRef De Kimpe L, van Haastert ES, Kaminari A, Zwart R, Rutjes H, Hoozemans JJM, Scheper W. Intracellular accumulation of aggregated pyroglutamate amyloid beta: convergence of aging and Aβ pathology at the lysosome. Age. 2013;35(3):673–87.CrossRef
26.
go back to reference Russo C, Violani E, Salis S, Venezia V, Dolcini V, Damonte G, Benatti U, D'Arrigo C, Patrone E, Carlo P, et al. Pyroglutamate-modified amyloid β-peptides – AβN3(pE) – strongly affect cultured neuron and astrocyte survival. J Neurochem. 2002;82(6):1480–9.CrossRef Russo C, Violani E, Salis S, Venezia V, Dolcini V, Damonte G, Benatti U, D'Arrigo C, Patrone E, Carlo P, et al. Pyroglutamate-modified amyloid β-peptides – AβN3(pE) – strongly affect cultured neuron and astrocyte survival. J Neurochem. 2002;82(6):1480–9.CrossRef
27.
go back to reference Jawhar S, Wirths O, Bayer TA. Pyroglutamate amyloid-beta (Abeta): a hatchet man in Alzheimer disease. J Biol Chem. 2011;286(45):38825–32.CrossRef Jawhar S, Wirths O, Bayer TA. Pyroglutamate amyloid-beta (Abeta): a hatchet man in Alzheimer disease. J Biol Chem. 2011;286(45):38825–32.CrossRef
28.
go back to reference Rubio-Perez JM, Morillas-Ruiz JM. A review: inflammatory process in Alzheimer's disease, role of cytokines. Scientific World J. 2012;2012:756357.CrossRef Rubio-Perez JM, Morillas-Ruiz JM. A review: inflammatory process in Alzheimer's disease, role of cytokines. Scientific World J. 2012;2012:756357.CrossRef
29.
go back to reference Montine TJ, Milatovic D, Gupta RC, Valyi-Nagy T, Morrow JD, Breyer RM. Neuronal oxidative damage from activated innate immunity is EP2 receptor-dependent. J Neurochem. 2002;83(2):463–70.CrossRef Montine TJ, Milatovic D, Gupta RC, Valyi-Nagy T, Morrow JD, Breyer RM. Neuronal oxidative damage from activated innate immunity is EP2 receptor-dependent. J Neurochem. 2002;83(2):463–70.CrossRef
30.
go back to reference Gadient RA, Otten UH. Interleukin-6 (IL-6)-a molecule with both beneficial and destructive potentials. Prog Neurobiol. 1997;52(5):379–90.CrossRef Gadient RA, Otten UH. Interleukin-6 (IL-6)-a molecule with both beneficial and destructive potentials. Prog Neurobiol. 1997;52(5):379–90.CrossRef
31.
go back to reference Zheng C, Zhou X-W, Wang J-Z. The dual roles of cytokines in Alzheimer’s disease: update on interleukins, TNF-α, TGF-β and IFN-γ. Transl Neurodegener. 2016;5:7.CrossRef Zheng C, Zhou X-W, Wang J-Z. The dual roles of cytokines in Alzheimer’s disease: update on interleukins, TNF-α, TGF-β and IFN-γ. Transl Neurodegener. 2016;5:7.CrossRef
32.
go back to reference Lawson LJ, Perry VH, Dri P, Gordon S. Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience. 1990;39(1):151–70.CrossRef Lawson LJ, Perry VH, Dri P, Gordon S. Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience. 1990;39(1):151–70.CrossRef
33.
go back to reference Perry VH, Teeling J. Microglia and macrophages of the central nervous system: the contribution of microglia priming and systemic inflammation to chronic neurodegeneration. Semin Immunopathol. 2013;35(5):601–12.CrossRef Perry VH, Teeling J. Microglia and macrophages of the central nervous system: the contribution of microglia priming and systemic inflammation to chronic neurodegeneration. Semin Immunopathol. 2013;35(5):601–12.CrossRef
Metadata
Title
Transplantation of bone marrow derived macrophages reduces markers of neuropathology in an APP/PS1 mouse model
Authors
Luís Costa-Marques
Katrin Arnold
Marie-Christine Pardon
Christiane Leovsky
Samantha Swarbrick
Claire Fabian
Alexandra Stolzing
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Translational Neurodegeneration / Issue 1/2019
Electronic ISSN: 2047-9158
DOI
https://doi.org/10.1186/s40035-019-0173-9

Other articles of this Issue 1/2019

Translational Neurodegeneration 1/2019 Go to the issue