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Neuron. 2018 Sep 5;99(5):925-940.e7. doi: 10.1016/j.neuron.2018.07.039.

Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer's Disease.

Author information

1
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
2
Brain Science Institute, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
3
Biozentrum, University of Basel, Basel 4056, Switzerland.
4
Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
5
Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA.
6
Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
7
German Center for Neurodegenerative Diseases (DZNE) and CAESAR Research Center, 53175 Bonn, Germany.
8
Institute for Research in Biomedicine, Barcelona 08028, Spain.
9
Brain Science Institute, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA. Electronic address: jrothstein@jhmi.edu.
10
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Electronic address: bhyman@mgh.harvard.edu.

Abstract

Tau is the major constituent of neurofibrillary tangles in Alzheimer's disease (AD), but the mechanism underlying tau-associated neural damage remains unclear. Here, we show that tau can directly interact with nucleoporins of the nuclear pore complex (NPC) and affect their structural and functional integrity. Pathological tau impairs nuclear import and export in tau-overexpressing transgenic mice and in human AD brain tissue. Furthermore, the nucleoporin Nup98 accumulates in the cell bodies of some tangle-bearing neurons and can facilitate tau aggregation in vitro. These data support the hypothesis that tau can directly interact with NPC components, leading to their mislocalization and consequent disruption of NPC function. This raises the possibility that NPC dysfunction contributes to tau-induced neurotoxicity in AD and tauopathies.

KEYWORDS:

Alzheimer’s disease; Nup98; nuclear pore complex; nucleocytoplasmic transport; tauopathies

PMID:
30189209
PMCID:
PMC6240334
[Available on 2019-09-05]
DOI:
10.1016/j.neuron.2018.07.039
[Indexed for MEDLINE]

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