Sustained arginase 1 expression modulates pathological tau deposits in a mouse model of tauopathy

Jerry B. Hunt, Kevin R. Nash, Devon Placides, Peter Moran, Maj Linda B. Selenica, Firas Abuqalbeen, Kevin Ratnasamy, Nina Slouha, Santiago Rodriguez-Ospina, Miloni Savlia, Yashobha Ranaweera, Patrick Reid, Chad A.Dickey Rodrigo Uricia, Clement G.Y. Yang, Leslie A. Sandusky, Marcia N. Gordon, Dave Morgan, Daniel C. Lee

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Tau accumulation remains one of the closest correlates of neuronal loss in Alzheimer’s disease. In addition, tau associates with several other neurodegenerative diseases, collectively known as tauopathies, in which clinical phenotypes manifest as cognitive impairment, behavioral disturbances, and motor impairment. Polyamines act as bivalent regulators of cellular function and are involved in numerous biological processes. The regulation of the polyamines system can become dysfunctional during disease states. Arginase 1 (Arg1) and nitric oxide synthases compete for L-arginine to produce either polyamines or nitric oxide, respectively. Herein, we show that overexpression of Arg1 using adeno-associated virus (AAV) in the CNS of rTg4510 tau transgenic mice significantly reduced phospho-tau species and tangle pathology. Sustained Arg1 overexpression decreased several kinases capable of phosphorylating tau, decreased inflammation, and modulated changes in the mammalian target of rapamycin and related proteins, suggesting activation of autophagy. Arg1 overexpression also mitigated hippocampal atrophy in tau transgenic mice. Conversely, conditional deletion of Arg1 in myeloid cells resulted in increased tau accumulation relative to Arg1-sufficient mice after transduction with a recombinant AAV–tau construct. These data suggest that Arg1 and the polyamine pathway may offer novel therapeutic targets for tauopathies.

Original languageEnglish
Pages (from-to)14842-14860
Number of pages19
JournalJournal of Neuroscience
Volume35
Issue number44
DOIs
StatePublished - Nov 4 2015

Bibliographical note

Publisher Copyright:
© 2015 the authors.

Keywords

  • Arginase
  • Autophagy
  • Inflammation
  • Kinase
  • Polyamine
  • Tau

ASJC Scopus subject areas

  • Neuroscience (all)

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