title: Sustained Arginase 1 Expression Modulates Pathological Tau Deposits in a Mouse Model of Tauopathy.
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.
authors.affiliation: Byrd Alzheimer's Institute, College of Pharmacy and Pharmaceutical Sciences, and.
authors.forename: Jerry B
authors.initials: JB
authors.lastname: Hunt
authors.affiliation: Byrd Alzheimer's Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida 33613.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Nash
authors.affiliation: Byrd Alzheimer's Institute, College of Pharmacy and Pharmaceutical Sciences, and.
authors.forename: Devon
authors.initials: D
authors.lastname: Placides
authors.affiliation: Byrd Alzheimer's Institute.
authors.forename: Peter
authors.initials: P
authors.lastname: Moran
authors.affiliation: Byrd Alzheimer's Institute, College of Pharmacy and Pharmaceutical Sciences, and.
authors.forename: Maj-Linda B
authors.initials: ML
authors.lastname: Selenica
authors.affiliation: Byrd Alzheimer's Institute, College of Pharmacy and Pharmaceutical Sciences, and.
authors.forename: Firas
authors.initials: F
authors.lastname: Abuqalbeen
authors.affiliation: Byrd Alzheimer's Institute, College of Pharmacy and Pharmaceutical Sciences, and.
authors.forename: Kevin
authors.initials: K
authors.lastname: Ratnasamy
authors.affiliation: Byrd Alzheimer's Institute, College of Pharmacy and Pharmaceutical Sciences, and.
authors.forename: Nina
authors.initials: N
authors.lastname: Slouha
authors.affiliation: Byrd Alzheimer's Institute.
authors.forename: Santiago
authors.identifier: http://orcid.org/0000-0003-0851-6864
authors.initials: S
authors.lastname: Rodriguez-Ospina
authors.affiliation: Byrd Alzheimer's Institute.
authors.forename: Miloni
authors.initials: M
authors.lastname: Savlia
authors.affiliation: Byrd Alzheimer's Institute, College of Pharmacy and Pharmaceutical Sciences, and.
authors.forename: Yashobha
authors.initials: Y
authors.lastname: Ranaweera
authors.affiliation: Byrd Alzheimer's Institute.
authors.forename: Patrick
authors.initials: P
authors.lastname: Reid
authors.affiliation: Byrd Alzheimer's Institute.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Dickey
authors.affiliation: Byrd Alzheimer's Institute, College of Pharmacy and Pharmaceutical Sciences, and.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Uricia
authors.affiliation: Morsani College of Medicine, University of South Florida, Tampa, Florida 33613.
authors.forename: Clement G Y
authors.initials: CG
authors.lastname: Yang
authors.affiliation: Byrd Alzheimer's Institute, College of Pharmacy and Pharmaceutical Sciences, and.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Sandusky
authors.affiliation: Byrd Alzheimer's Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida 33613.
authors.forename: Marcia N
authors.identifier: http://orcid.org/0000-0002-4051-9283
authors.initials: MN
authors.lastname: Gordon
authors.affiliation: Byrd Alzheimer's Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida 33613.
authors.forename: Dave
authors.initials: D
authors.lastname: Morgan
authors.affiliation: Byrd Alzheimer's Institute, College of Pharmacy and Pharmaceutical Sciences, and dlee1@health.usf.edu.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Lee
mesh_terms: D000818:Animals; D001119:Arginase / Q000096:biosynthesis* / Q000235:genetics; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D006367:HeLa Cells; D006624:Hippocampus / Q000201:enzymology / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D024801:Tauopathies / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016875:tau Proteins; C544448:Arg1 protein, mouse; D001119:Arginase
keywords: arginase; autophagy; inflammation; kinase; polyamine; tau