Volume 6 Supplement 2

53rd Annual Meeting of the Society for Research into Hydrocephalus and Spina Bifida

Open Access

Microglial downregulation in a double transgenic mouse model associated with early-onset Alzheimer's disease (AD) after intraventricular implantation of alginate encapsulated Glukagon-like-peptide-1 (GLP-1) producing human mesenchymal stem-cells

  • Kathrin Harmening1,
  • Anna Heile1,
  • Miles Miller2,
  • Conrad E Johanson2,
  • Christine Wallrapp3,
  • Thomas Brinker1,
  • Gerald D Silverberg2 and
  • Petra M Klinge2Email author
Cerebrospinal Fluid Research20096(Suppl 2):S15

https://doi.org/10.1186/1743-8454-6-S2-S15

Published: 27 November 2009

Background

GLP-1 peptide is an endogenous insulinotropic peptide. GLP-1 receptors are expressed throughout the brains of rodents and humans. Intracerebroventricular GLP-1 administration reduced the levels of amyloid-beta peptide (Aβ) in diabetic mice and protected cultured hippocampal neurons against Aβ and iron induced stress suggesting that GLP-1 can modify amyloid precursor protein (APP) processing and protect against oxidative injury [1]. In the double transgenic mice model associated with early-onset AD, the effect of GLP-1 secreting human mesenchymal stem cells (hMSC) on A-β40/42 load, Aβ associated gliosis and microglial response were investigated in the present study.

Materials and methods

Alginate microcapsules (CellBeads®) containing "native" (CB085) or GLP-1 transfected hMSCs (CB087) were stereotactically implanted into the right ventricle of double transgenic mice mutant expressing APP and presenelin-1 protein (APPswe, PSEN1dEG; JACKSON LAB) at 27 weeks of age (n = 14 each). After 8 weeks of implantation (i.e. 35 weeks of age), brains of 4 animals per group were processed for histological assessment using Antibodies against Aβ40/42 (polyclonal; US BIOLOGICAL), glial fibrillary acidic protein (GFAP polyclonal, DAKO) and the microglial marker CD11b (monoclonal; BIOMOL). The remaining brains were used for Aβ40/42 ELIZA. N= 7 35-36 weeks old Tg-mice provided the age-matched early-onset AD controls.

Results

Total counts of Aβ40/42 positively stained plaques assessed in the frontal cortex were reduced in the animals with GLP-1 transfected CellBeads® implants when compared to the "native" stem-cell group and the control:107 ± 24 (GLP-1 hMSCs) vs. 165 ± 44 ("native" hMSCs) vs. 140 (control, n = 1); p = 0.07 (t-test of GLP-1 vs. "native" hMSCs). Likewise, the number of reactive astrocytes (> three GFAP positively stained processes) measured in the dentate gyrus of the hippocampus showed a tendency towards a lower count in GLP-1 CellBeads® mice. Morphometric analysis of CD11b positively stained particles per cortical area (%) showed most striking evidence in group differences: animals with GLP-1 transfected CellBeads® showed a significant reduction of microglial immunoreactivity against age-matched AD control: 0.28 ± 0.14% vs. 0.58 ± 0.05% (p = 0.02, t-test). "Native" CellBeads® showed a reduced but not significant change in the microglial response.

Conclusion

GLP-1 producing stem cells encapsulated in alginate have lowered Aβ40/42 load in a mouse model of early-onset AD, which corresponded to a significant down-regulation of specific microglial-type changes in that model.

Authors’ Affiliations

(1)
International Neuroscience Institute GmbH
(2)
Department of Clinical Neuroscience, Alpert Medical School at Brown University, Rhode Island Hospital
(3)
Cellmed AG

References

  1. Perry T, Lahiri DK, Sambamurti K, Chen D, Mattson MP, Egan JM, Greig NH: Glucagon-like peptide-1 decreases endogenous amyloid-beta peptide (Abeta) levels and protects hippocampal neurons from death induced by Abeta and iron. J Neurosci Res. 2003, 72: 603-612. 10.1002/jnr.10611.View ArticlePubMedGoogle Scholar

Copyright

© Harmening et al; licensee BioMed Central Ltd. 2009

This article is published under license to BioMed Central Ltd.

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