Cre-inducible Adeno Associated Virus-mediated Expression of P301L Mutant Tau Causes Motor Deficits and Neuronal Degeneration in the Substantia Nigra.
Neuroscience. 2019-12-01; 422: 65-74
DOI: 10.1016/j.neuroscience.2019.10.001
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1. Neuroscience. 2019 Dec 1;422:65-74. doi: 10.1016/j.neuroscience.2019.10.001. Epub
2019 Nov 2.
Cre-inducible Adeno Associated Virus-mediated Expression of P301L Mutant Tau
Causes Motor Deficits and Neuronal Degeneration in the Substantia Nigra.
You Y(1), Botros MB(2), Enoo AAV(3), Bockmiller A(4), Herron S(5), Delpech JC(6),
Ikezu T(7).
Author information:
(1)Department of Pharmacology & Experimental Therapeutics, Boston University
School of Medicine, Boston, MA, USA. Electronic address: .
(2)Department of Pharmacology & Experimental Therapeutics, Boston University
School of Medicine, Boston, MA, USA. Electronic address: .
(3)Department of Pharmacology & Experimental Therapeutics, Boston University
School of Medicine, Boston, MA, USA. Electronic address: .
(4)Department of Pharmacology & Experimental Therapeutics, Boston University
School of Medicine, Boston, MA, USA. Electronic address: .
(5)Department of Pharmacology & Experimental Therapeutics, Boston University
School of Medicine, Boston, MA, USA. Electronic address: .
(6)Department of Pharmacology & Experimental Therapeutics, Boston University
School of Medicine, Boston, MA, USA. Electronic address: .
(7)Department of Pharmacology & Experimental Therapeutics, Boston University
School of Medicine, Boston, MA, USA; Department of Neurology, Boston University
School of Medicine, Boston, MA, USA; Center for Systems Neuroscience, Boston
University, Boston, MA. Electronic address: .
Accumulation of microtubule associated protein tau in the substantia nigra is
associated with several tauopathies including progressive supranuclear palsy
(PSP). A number of studies have used mutant tau transgenic mouse model to mimic
the neuropathology of tauopathies and disease phenotypes. However, tau expression
in these transgenic mouse models is not specific to brain subregions, and may not
recapitulate subcortical disease phenotypes of PSP. It is necessary to develop a
new disease modeling system for cell and region-specific expression of pathogenic
tau for modeling PSP in mouse brain. In this study, we developed a novel strategy
to express P301L mutant tau to the dopaminergic neurons of substantia nigra by
coupling tyrosine hydroxylase promoter Cre-driver mice with a Cre-inducible
adeno-associated virus (iAAV). The results showed that P301L mutant tau was
successfully transduced in the dopaminergic neurons of the substantia nigra at
the presence of Cre recombinase and iAAV. Furthermore, the iAAV-tau-injected mice
displayed severe motor deficits including impaired movement ability, motor
balance, and motor coordination compared to the control groups over a short
time-course. Immunochemical analysis revealed that tau gene transfer
significantly resulted in loss of tyrosine hydroxylase-positive dopaminergic
neurons and elevated phosphorylated tau in the substantia nigra. Our development
of dopaminergic neuron-specific neurodegenerative mouse model with tauopathy will
be helpful for studying the underlying mechanism of pathological protein
propagation as well as development of new therapies.
Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.neuroscience.2019.10.001
PMCID: PMC6898791 [Available on 2020-12-01]
PMID: 31689387 [Indexed for MEDLINE]