title: In vivo axonal transport deficits in a mouse model of fronto-temporal dementia.
abstract: BACKGROUND
  Axonal transport is vital for neurons and deficits in this process have been previously reported in a few mouse models of Alzheimer's disease prior to the appearance of plaques and tangles. However, it remains to be determined whether axonal transport is defective prior to the onset of neurodegeneration. The rTg4510 mouse, a fronto-temporal dementia and parkinsonism-17 (FTDP-17) tauopathy model, over-express tau-P301L mutation found in familial forms of FTDP-17, in the forebrain driven by the calcium-calmodulin kinase II promoter. This mouse model exhibits tau pathology, neurodegeneration in the forebrain, and associated behavioral deficits beginning at 4-5 months of age.
  rTg4510 transgenic mice were used in these studies. Mice were given 2 μL of MnCl2 in each nostril 1 h prior to Magnetic Resonance Imaging (MRI). Following MnCl2 nasal lavage, mice were imaged using Manganese enhanced Magnetic Resonance Imaging (MEMRI) Protocol with TE = 8.5 ms, TR = 504 ms, FOV = 3.0 cm, matrix size = 128 × 128 × 128, number of cycles = 15 with each cycle taking approximately 2 min, 9 s, and 24 ms using Paravision software (BrukerBioSpin, Billerica, MA). During imaging, body temperature was maintained at 37.0 °C using an animal heating system (SA Instruments, Stony Brook, NY).
  
  
  METHODS
  Resulting images were analyzed using Paravision software. Regions of interest (ROI) within the olfactory neuronal layer (ONL) and the water phantom consisting of one pixel (ONL) and 9 pixels (water) were selected and copied across each of the 15 cycles. Signal intensities (SI) of ONL and water phantom ROIs were measured. SI values obtained for ONL were then normalized the water phantom SI values. The correlation between normalized signal intensity in the ONL and time were assessed using Prism (GraphPad Software, San Diego, CA).
  
  
  RESULTS
  Using the MEMRI technique on 1.5, 3, 5, and 10-month old rTg4510 mice and littermate controls, we found significant axonal transport deficits present in the rTg4510 mice beginning at 3 months of age in an age-dependent manner. Using linear regression analysis, we measured rates of axonal transport at 1.5, 3, 5, and 10 months of age in rTg4510 and WT mice. Axonal transport rates were observed in rTg4510 mice at 48% of WT levels at 3 months, 40% of WT levels at 5 months, and 30% of WT levels at 10 months of age. In order to determine the point at which tau appears in the cortex, we probed for phosphorylated tau levels, and found that pSer262 is present at 3 months of age, not earlier at 1.5 months of age, but observed no pathological tau species until 6 months of age, months after the onset of the transport deficits. In addition, we saw localization of tau in the ONL at 6 months of age.
  
  
  CONCLUSIONS
  In our study, we identified the presence of age-dependent axonal transport deficits beginning at 3 months of age in rTg4510 mice. We correlated these deficits at 3 months to the presence of hyperphosphorylated tau in the brain and the presence within the olfactory epithelium. We observed tau pathology not only in the soma of these neurons but also within the axons and processes of these neurons. Our characterization of axonal transport in this tauopathy model provides a functional time point that can be used for future therapeutic interventions.
authors.affiliation: Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA ; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, USA.
authors.forename: Tabassum
authors.initials: T
authors.lastname: Majid
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA ; The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA.
authors.forename: Yousuf O
authors.initials: YO
authors.lastname: Ali
authors.affiliation: Institute for Applied Cancer Science, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Deepa V
authors.initials: DV
authors.lastname: Venkitaramani
authors.affiliation: Institute for Applied Cancer Science, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ming-Kuei
authors.initials: MK
authors.lastname: Jang
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA ; The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA ; Developmental Biology Program, Baylor College of Medicine, Houston, TX, USA ; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Hui-Chen
authors.initials: HC
authors.lastname: Lu
authors.affiliation: Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA ; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, USA ; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Robia G
authors.initials: RG
authors.lastname: Pautler
mesh_terms: D000367:Age Factors; D000818:Animals; D001370:Axonal Transport / Q000502:physiology*; D001369:Axons / Q000378:metabolism*; D001921:Brain / Q000473:pathology*; D004195:Disease Models, Animal; D057180:Frontotemporal Dementia / Q000235:genetics / Q000473:pathology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D051842:Olfactory Marker Protein / Q000378:metabolism; D009833:Olfactory Pathways / Q000473:pathology*; D013997:Time Factors; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D005904:Glial Fibrillary Acidic Protein; C054369:MAPT protein, human; D051842:Olfactory Marker Protein; D016875:tau Proteins
keywords: Alzheimer's disease; Axonal transport; Fronto-temporal dementia; MEMRI; MRI; Tau