Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer’s disease or corticobasal degeneration brains
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Filamentous tau pathologies are hallmark lesions of several neurodegenerative tauopathies including Alzheimer’s disease (AD) and corticobasal degeneration (CBD) which show cell type-specific and topographically distinct tau inclusions. Growing evidence supports templated transmission of tauopathies through functionally interconnected neuroanatomical pathways suggesting that different self-propagating strains of pathological tau could account for the diverse manifestations of neurodegenerative tauopathies. Here, we describe the rapid and distinct cell type-specific spread of pathological tau following intracerebral injections of CBD or AD brain extracts enriched in pathological tau (designated CBD-Tau and AD-Tau, respectively) in young human mutant P301S tau transgenic (Tg) mice (line PS19) ~6–9 months before they show onset of mutant tau transgene-induced tau pathology. At 1 month post-injection of CBD-Tau, tau inclusions developed predominantly in oligodendrocytes of the fimbria and white matter near the injection sites with infrequent intraneuronal tau aggregates. In contrast, injections of AD-Tau in young PS19 mice induced tau pathology predominantly in neuronal perikarya with little or no oligodendrocyte involvement 1 month post-injection. With longer post-injection survival intervals of up to 6 months, CBD-Tau- and AD-Tau-induced tau pathology spread to different brain regions distant from the injection sites while maintaining the cell type-specific pattern noted above. Finally, CA3 neuron loss was detected 3 months post-injection of AD-Tau but not CBD-Tau. Thus, AD-Tau and CBD-Tau represent specific pathological tau strains that spread differentially and may underlie distinct clinical and pathological features of these two tauopathies. Hence, these strains could become targets to develop disease-modifying therapies for CBD and AD.
KeywordsAlzheimer’s disease Corticobasal degeneration Seeded transmission of pathological tau Frontotemporal degeneration
Susana Boluda was supported by Bolsa de Ampliación de Estudios (BA11/00021) from the Spanish government, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, Madrid, Spain. This work was supported by the CurePSP Foundation, NIH grant AG17586, the Marian S. Ware Alzheimer Program, the Karen Cohen Segal, the Eleanor Margaret Kurtz Endowed Fund, the Mary Rasmus Endowed Fund for Alzheimer’s Research, Mrs. Gloria J. Miller and Arthur Peck, M.D. We thank Theresa Schuck, John Robinson and Jennifer McBride for their technical assistance in immunohistochemistry, Linda Kwong for her technical assistance in biochemistry procedures and reading of this manuscript, Sue Leight for her technical assistance in mouse manipulation, Magdalena Nitla for her technical assistance in mouse injections and Young Baek and Rui Tong for data management.
Conflict of interest
The authors declare that they have no conflict of interest.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.
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