In vivo axonal transport deficits in a mouse model of fronto-temporal dementia

Abstract

BackgroundAxonal 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.Animal modelrTg4510 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).Data analysisResulting 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).ResultsUsing 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.DiscussionIn 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...

Identification of changes in neuronal function as a consequence of aging and tauopathic neurodegeneration using a novel and sensitive magnetic resonance imaging approach

“…MEMRI successfully detected differences in AD mouse models overexpressing APP (Smith et al, 2007) and has been used to examine axonal transport rates in olfactory bulbs of rTg4510 (Majid et al, 2014). Because cognitive decline is closely associated with pathogenic tau accumulation, we used rTg4510 mice to identify whether MEMRI specifically detects changes in regions of the brain negatively impacted by tauopathy.…”

“…Other studies employing MEMRI to measure changes in rTg4510 mice have also shown important differences. In one instance, MEMRI was used to measure transport rates and tract tracing in the olfactory bulb and showed that rTg4510 mice present transport deficits along olfactory axons (Majid et al, 2014). These data in the olfactory tract suggest and support our findings that there are neuronal deficits in the hippocampus of tau transgenic mice.…”

Hippocampal to basal forebrain transport of Mn 2+ is impaired by deletion of KLC1, a subunit of the conventional kinesin microtubule-based motor

“…Our work in the optic tract demonstrated that KLC1-dependent transport represented only a third of the total Mn 2+ transport (Bearer et al, 2007a). Thus, MEMRI can be used to study transport dynamics during progression or experimental treatment of neurodegenerative disease in pre-clinical animal models without particular organelle or specific motor bias, where particular focus has been on accumulation in the olfactory bulb after nasal delivery (Cross et al, 2008; Majid et al, 2014; Pautler et al, 1998; Smith et al, 2007; Smith et al, 2011; Wang et al, 2012). …”

Repeated exposure to chlorpyrifos leads to prolonged impairments of axonal transport in the living rodent brain

“…Thus far, the technique has been successfully used to detect impairments of axonal transport in the brains of aged rats (Cross et al, 2008), mouse models of Alzheimer's disease (Kim et al, 2011;Smith et al, 2007Smith et al, , 2011, frontotemporal dementia (Majid et al, 2014), and mice homozygous for a deletion in the amyloid precursor protein gene (Gallagher et al, 2012). MEMRI exploits both the paramagnetic properties of Mn 2+ and its ability to serve as a calcium analog in neurons.…”