Organotypic Hippocampal Slice Cultures from Adult Tauopathy Mice and Theragnostic Evaluation of Nanomaterial Phospho-TAU Antibody-Conjugates
Susanna Kemppainen,
Nadine Huber,
Roosa-Maria Willman,
Ana Zamora,
Petra Mäkinen,
Henna Martiskainen,
Mari Takalo,
Annakaisa Haapasalo,
Tomás Sobrino,
Manuel Antonio González Gómez,
Yolanda Piñeiro,
José Rivas,
Uwe Himmelreich,
Mikko Hiltunen
Affiliations
Susanna Kemppainen
Institute of Biomedicine, University of Eastern Finland, 70211 Kuopio, Finland
Nadine Huber
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland
Roosa-Maria Willman
Institute of Biomedicine, University of Eastern Finland, 70211 Kuopio, Finland
Ana Zamora
Molecular Imaging and Photonics, KU Leuven, 3001 Leuven, Belgium
Petra Mäkinen
Institute of Biomedicine, University of Eastern Finland, 70211 Kuopio, Finland
Henna Martiskainen
Institute of Biomedicine, University of Eastern Finland, 70211 Kuopio, Finland
Mari Takalo
Institute of Biomedicine, University of Eastern Finland, 70211 Kuopio, Finland
Annakaisa Haapasalo
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland
Tomás Sobrino
NeuroAging Group (NEURAL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
Manuel Antonio González Gómez
Institute of Materials, Applied Physics Department, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Yolanda Piñeiro
Institute of Materials, Applied Physics Department, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
José Rivas
Institute of Materials, Applied Physics Department, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Uwe Himmelreich
Biomedical MRI, Department of Imaging and Pathology, KU Leuven, 3000 Leuven, Belgium
Mikko Hiltunen
Institute of Biomedicine, University of Eastern Finland, 70211 Kuopio, Finland
Organotypic slice culture models surpass conventional in vitro methods in many aspects. They retain all tissue-resident cell types and tissue hierarchy. For studying multifactorial neurodegenerative diseases such as tauopathies, it is crucial to maintain cellular crosstalk in an accessible model system. Organotypic slice cultures from postnatal tissue are an established research tool, but adult tissue-originating systems are missing, yet necessary, as young tissue-originating systems cannot fully model adult or senescent brains. To establish an adult-originating slice culture system for tauopathy studies, we made hippocampal slice cultures from transgenic 5-month-old hTau.P301S mice. In addition to the comprehensive characterization, we set out to test a novel antibody for hyperphosphorylated TAU (pTAU, B6), with and without a nanomaterial conjugate. Adult hippocampal slices retained intact hippocampal layers, astrocytes, and functional microglia during culturing. The P301S-slice neurons expressed pTAU throughout the granular cell layer and secreted pTAU to the culture medium, whereas the wildtype slices did not. Additionally, cytotoxicity and inflammation-related determinants were increased in the P301S slices. Using fluorescence microscopy, we showed target engagement of the B6 antibody to pTAU-expressing neurons and a subtle but consistent decrease in intracellular pTAU with the B6 treatment. Collectively, this tauopathy slice culture model enables measuring the extracellular and intracellular effects of different mechanistic or therapeutic manipulations on TAU pathology in adult tissue without the hindrance of the blood–brain barrier.
