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Neurobiol Dis. 2015 Jan;73:83-95. doi: 10.1016/j.nbd.2014.08.032. Epub 2014 Sep 16.

Intracerebral injection of preformed synthetic tau fibrils initiates widespread tauopathy and neuronal loss in the brains of tau transgenic mice.

Author information

1
Department of Neuroscience, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, B-2340 Beerse, Belgium.
2
UCLouvain, Institute of Neuroscience, Group of Cellular and Molecular Neuroscience, B-1200 Woluwe-Saint-Lambert, Belgium.
3
Histogenex, B-2020 Antwerp, Belgium.
4
Center for Neurodegenerative Disease Research, Institute on Aging, Department of Pathology and Laboratory, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
5
Department of Neuroscience, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, B-2340 Beerse, Belgium. Electronic address: dmoechar@its.jnj.com.

Abstract

Neurofibrillary tangles composed of hyperphosphorylated fibrillized tau are found in numerous tauopathies including Alzheimer's disease. Increasing evidence suggests that tau pathology can be transmitted from cell-to-cell; however the mechanisms involved in the initiation of tau fibrillization and spreading of disease linked to progression of tau pathology are poorly understood. We show here that intracerebral injections of preformed synthetic tau fibrils into the hippocampus or frontal cortex of young tau transgenic mice expressing mutant human P301L tau induces tau hyperphosphorylation and aggregation around the site of injection, as well as a time-dependent propagation of tau pathology to interconnected brain areas distant from the injection site. Furthermore, we show that the tau pathology as a consequence of injection of tau preformed fibrils into the hippocampus induces selective loss of CA1 neurons. Together, our data confirm previous studies on the seeded induction and the spreading of tau pathology in a different tau transgenic mouse model and reveals neuronal loss associated with seeded tau pathology in tau transgenic mouse brain. These results further validate the utility of the tau seeding model in studying disease transmission, and provide a more complete in vivo tauopathy model with associated neurodegeneration which can be used to investigate the mechanisms involved in tau aggregation and spreading, as well as aid in the search for disease modifying treatments for Alzheimer's disease and related tauopathies.

KEYWORDS:

Cell death; Seeding; Spreading; Tau pathology

PMID:
25220759
PMCID:
PMC4303592
DOI:
10.1016/j.nbd.2014.08.032
[Indexed for MEDLINE]
Free PMC Article

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