12 | Endothelial-macrophage interaction in human Alzheimer-patient-specific blood-brain barrier models

To promote clinical translation, we have generated iPSC-derived endothelial cells, pericytes, astrocytes and microglia that will be used to establish a 3D human disease-specific model of the BBB. In the co-culture, endothelial cells and astrocytes secrete extracellular matrix proteins to generate and maintain the basement membrane. By adding iPSC-derived microglia and macrophages on the parenchymal side and monocytes on the vascular side of the model, we will be able to investigate the interaction of monocyte/macrophages and endothelial cells at the BBB in a disease-specific manner. The model will be further refined by using patient-derived cells.

Publications

  • Oksanen M, Petersen AJ, Naumenko N, Puttonen K, Lehtonen Š, Gubert Olivé M, Shakirzyanova A, Leskelä S, Sarajärvi T, Viitanen M, Rinne JO, Hiltunen M, Haapasalo A, Giniatullin R, Tavi P, Zhang SC, Kanninen KM, Hämäläinen RH, Koistinaho J. PSEN1 mutant iPSC-derived model reveals severe astrocyte pathology in Alzheimer's disease. Stem Cell Reports 2017;9:1885-1897.
  • Holmqvist S, Lehtonen Š, Chumarina M, Puttonen KA, Azevedo C, Lebedeva O, Ruponen M, Oksanen M, Collin A, Goldwurm S, Meyer M, Lagarkova M, Kiselev S, Koistinaho J, Roybon L. Creation of a library of induced pluripotent stem cells from Parkinsonian patients. NPJ Parkinsons Dis 2016;2:16009.
  • Huuskonen MT, Loppi S, Dhungana H, Keksa-Goldsteine V, Lemarchant S, Korhonen P, Wojciechowski S, Pollari E, Valonen P, Koponen J, Takashima A, Landreth G, Goldsteins G, Malm T, Koistinaho J, Kanninen KM. Bexarotene targets autophagy and is protective against thromboembolic stroke in aged mice with tauopathy. Sci Rep 2016;6:33176.
  • Kärkkäinen V, Pomeshchik Y, Savchenko E, Dhungana H, Kurronen A, Lehtonen S, Naumenko N, Tavi P, Levonen AL, Yamamoto M, Malm T, Magga J, Kanninen KM, Koistinaho J. Nrf2 regulates neurogenesis and protects neural progenitor cells against Aβ toxicity. Stem Cells 2014;32:1904-1916.
  • Kanninen K, Heikkinen R, Malm T, Rolova T, Kuhmonen S, Leinonen H, Ylä-Herttuala S, Tanila H, Levonen AL, Koistinaho M, Koistinaho J. Intrahippocampal injection of a lentiviral vector expressing Nrf2 improves spatial learning in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A 2009;106:16505-10.

Potential secondments

MIM (Paul Vulto), month 12-15; VUMC (Elga de Vries), month 20-21; UZL (Markus Schwaninger), month 26

Host Organisation:
Neuroscience Center, University of Helsinki, Finland
Supervisor: