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Proc Natl Acad Sci U S A. 2017 Dec 19;114(51):E11029-E11036. doi: 10.1073/pnas.1717193114. Epub 2017 Dec 4.

Evidence for sortilin modulating regional accumulation of human tau prions in transgenic mice.

Author information

1
Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California, San Francisco, CA 94158.
2
Department of Neurology, University of California, San Francisco, CA 94158.
3
Department of Pharmaceutical Chemistry and Mass Spectrometry Facility, University of California, San Francisco, CA 94158.
4
Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California, San Francisco, CA 94158; stanley.prusiner@ucsf.edu.
5
Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158.

Abstract

Misfolding of tau proteins into prions and their propagation along neural circuits are thought to result in neurodegeneration causing Alzheimer's disease, progressive supranuclear palsy, chronic traumatic encephalopathy, and other tauopathies. Little is known about the molecular processes mediating tau prion replication and spreading in different brain regions. Using transgenic (Tg) mice with a neuronal promoter driving expression of human mutant (P301S) tau, we found that tau prion formation and histopathologic deposition is largely restricted to the hindbrain. Unexpectedly, tau mRNA and protein levels did not differ between the forebrain and hindbrain, suggesting that other factors modulating the conversion of tau into a prion exist and are region specific. Using a cell-based prion propagation assay, we discovered that tau prion replication is suppressed by forebrain-derived inhibitors, one of which is sortilin, a lysosomal sorting receptor. We also show that sortilin expression is higher in the forebrain than the hindbrain across the life span of the Tg mice, suggesting that sortilin, at least in part, inhibits forebrain tau prion replication in vivo. Our findings provide evidence for selective vulnerability in mice resulting in highly regulated levels of tau prion propagation, thus affording a model for identification of additional molecules that could mitigate the levels of tau prions in human tauopathies.

KEYWORDS:

Alzheimer’s disease; neurodegeneration; prion; selective vulnerability; tau

PMID:
29203673
PMCID:
PMC5754811
DOI:
10.1073/pnas.1717193114
[Indexed for MEDLINE]
Free PMC Article

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