期刊
CELLS
卷 12, 期 10, 页码 -出版社
MDPI
DOI: 10.3390/cells12101422
关键词
organotypic slice culture; adult tissue; hyperphosphorylated TAU; P301S mice; ex vivo; theragnostic nanomaterials; immunotherapy
类别
Organotypic slice culture models, especially those derived from adult tissue, provide a valuable tool for studying neurodegenerative diseases such as tauopathies. In this study, hippocampal slice cultures from adult transgenic mice were used to investigate the effects of a novel antibody on hyperphosphorylated TAU. The adult-originating slices retained key cellular components and exhibited tau pathology, making them a suitable model for studying TAU pathology in the adult brain without the interference of the blood-brain barrier.
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.
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