title: Nmnat1 protects neuronal function without altering phospho-tau pathology in a mouse model of tauopathy.
abstract: The nicotinamide-nucleotide adenylyltransferase protein Nmnat1 is a potent inhibitor of axonal degeneration in models of acute axonal injury. Hyperphosphorylation and aggregation of the microtubule-associated protein Tau are associated with neurodegeneration in Alzheimer's Disease and other disorders. Previous studies have demonstrated that other Nmnat isoforms can act both as axonoprotective agents and have protein chaperone function, exerting protective effects in drosophila and mouse models of tauopathy. Nmnat1 targeted to the cytoplasm (cytNmnat1) is neuroprotective in a mouse model of neonatal hypoxia-ischemia, but the effect of cytNmnat1 on tauopathy remains unknown.
  
  
  
  We examined the impact of overexpression of cytNmnat1 on tau pathology, neurodegeneration, and brain functional connectivity in the P301S mouse model of chronic tauopathy.
  
  
  
  Overexpression of cytNmnat1 preserved cortical neuron functional connectivity in P301S mice in vivo. However, whereas Nmnat1 overexpression decreased the accumulation of detergent-insoluble tau aggregates in the cerebral cortex, it exerted no effect on immunohistochemical evidence of pathologic tau phosphorylation and misfolding, hippocampal atrophy, or inflammatory markers in P301S mice.
  
  
  
  Our results demonstrate that cytNmnat1 partially preserves neuronal function and decreases biochemically insoluble tau in a mouse model of chronic tauopathy without preventing tau phosphorylation, formation of soluble aggregates, or tau-induced inflammation and atrophy. Nmnat1 might thus represent a therapeutic target for tauopathies.
authors.affiliation: Departments of Neurology Washington University School of Medicine St. Louis Missouri; Hope Center for Neurological Disorders Washington University School of Medicine St. Louis Missouri; Knight Alzheimer's Disease Research Center Washington University School of Medicine St. Louis Missouri.
authors.forename: Erik S
authors.initials: ES
authors.lastname: Musiek
authors.affiliation: Departments of Neurology Washington University School of Medicine St. Louis Missouri; Hope Center for Neurological Disorders Washington University School of Medicine St. Louis Missouri; Knight Alzheimer's Disease Research Center Washington University School of Medicine St. Louis Missouri.
authors.forename: David D
authors.initials: DD
authors.lastname: Xiong
authors.affiliation: Departments of Neurology Washington University School of Medicine St. Louis Missouri; Hope Center for Neurological Disorders Washington University School of Medicine St. Louis Missouri; Knight Alzheimer's Disease Research Center Washington University School of Medicine St. Louis Missouri.
authors.forename: Tirth
authors.initials: T
authors.lastname: Patel
authors.affiliation: Genetics Washington University School of Medicine St. Louis Missouri.
authors.forename: Yo
authors.initials: Y
authors.lastname: Sasaki
authors.affiliation: Departments of Neurology Washington University School of Medicine St. Louis Missouri; Hope Center for Neurological Disorders Washington University School of Medicine St. Louis Missouri; Knight Alzheimer's Disease Research Center Washington University School of Medicine St. Louis Missouri.
authors.forename: Yinong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Radiology Washington University School of Medicine St. Louis Missouri.
authors.forename: Adam Q
authors.initials: AQ
authors.lastname: Bauer
authors.affiliation: Departments of Neurology Washington University School of Medicine St. Louis Missouri; Hope Center for Neurological Disorders Washington University School of Medicine St. Louis Missouri; Knight Alzheimer's Disease Research Center Washington University School of Medicine St. Louis Missouri.
authors.forename: Risham
authors.initials: R
authors.lastname: Singh
authors.affiliation: Departments of Neurology Washington University School of Medicine St. Louis Missouri; Hope Center for Neurological Disorders Washington University School of Medicine St. Louis Missouri; Knight Alzheimer's Disease Research Center Washington University School of Medicine St. Louis Missouri.
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Finn
authors.affiliation: Radiology Washington University School of Medicine St. Louis Missouri.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Culver
authors.affiliation: Genetics Washington University School of Medicine St. Louis Missouri.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Milbrandt
authors.affiliation: Departments of Neurology Washington University School of Medicine St. Louis Missouri; Hope Center for Neurological Disorders Washington University School of Medicine St. Louis Missouri; Knight Alzheimer's Disease Research Center Washington University School of Medicine St. Louis Missouri.
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman