Age-related decrease in axonal transport measured by MR imaging in vivo.
ABSTRACT Axonal transport is a crucial process for neuronal homeostasis and cell functions. In vitro studies have indicated transport rates decrease with age. Disruption of axonal transport has been implicated in age-associated neurodegenerative disorders. We hypothesized that aged rats would show decreased transport in the brain, which could be measured using in vivo manganese-enhanced MR imaging (Mn-MRI) and parametric estimation. Serial T1-weighted images were obtained at pre- and post-administration of MnCl(2) in rats scanned longitudinally (n=4) and in a separate aged group (n=3). Subtraction analysis was performed for group-wise statistical comparison on a pixel-by-pixel basis. Change in intensity over time was plotted for the olfactory bulb and anterior and posterior olfactory tract. Bulk transport of material was estimated over an initial 72 h. Tracer kinetic estimation of time-intensity data, based on a mass transport model, used intensity change in the bulb as input function for subsequent changes in the tract. Time to the peak of Mn(2+) flow was estimated for both anterior and posterior tracts. Results indicated age-related decreases in axonal transport rate and bulk transport of material in the olfactory tract of living rat brains. Longitudinally scanned, mid-age group was decreased by 58% and the aged group by 71% of young rate (neuronal transport=4.07+/-1.24 mm/h, 1.72+/-0.89 mm/h, and 1.16+/-0.18 mm/h for young, mid-age, and aged, respectively). Neuronal transport rate decreases correlated with increased age. The use of kinetic analysis combined with dynamic manganese enhanced MR imaging provides a unique opportunity to study this important neuronal process.
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ABSTRACT: Abnormalities and impairments in axonal transport are suggested to strongly contribute to the pathological alterations underlying AD. The exact mechanisms leading to axonopathy are currently unclear, but it was recently suggested that APP expression itself triggers axonal degeneration. We used APP transgenic mice and crossed them on a hemi- or homozygous PS1 knock-in background (APP/PS1KI). Depending on the mutant PS1 dosage, we demonstrate a clear aggravation in both plaque-associated and plaque-distant axonal degeneration, despite of an unchanged APP expression level. Amyloid-β (Aβ) peptides were found to accumulate in axonal swellings as well as in axons and apical dendrites proximate to neurons accumulating intraneuronal Aβ in their cell bodies. This suggests that Aβ can be transported within neurites thereby contributing to axonal deficits. In addition, diffuse extracellular Aβ deposits were observed in the close vicinity of axonal spheroids accumulating intracellular Aβ, which might be indicative of a local Aβ release from sites of axonal damage.Frontiers in Aging Neuroscience 01/2014; 6:139. · 5.20 Impact Factor
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ABSTRACT: Optic neuritis is frequently the first symptom of multiple sclerosis (MS), an inflammatory demyelinating neurodegenerative disease. Impaired axonal transport has been considered as an early event of neurodegenerative diseases. However, few studies have assessed the integrity of axonal transport in MS or its animal models. We hypothesize that axonal transport impairment occurs at the onset of optic neuritis in experimental autoimmune encephalomyelitis (EAE) mice. In this study, we employed manganese-enhanced MRI (MEMRI) to assess axonal transport in optic nerves in EAE mice at the onset of optic neuritis. Axonal transport was assessed as (a) optic nerve Mn(2+) accumulation rate (in % signal change/hour) by measuring the rate of increased total optic nerve signal enhancement, and (b) Mn(2+) transport rate (in mm/hour) by measuring the rate of change in optic nerve length enhanced by Mn(2+). Compared to sham-treated healthy mice, Mn(2+) accumulation rate was significantly decreased by 19% and 38% for EAE mice with moderate and severe optic neuritis, respectively. The axonal transport rate of Mn(2+) was significantly decreased by 43% and 65% for EAE mice with moderate and severe optic neuritis, respectively. The degree of axonal transport deficit correlated with the extent of impaired visual function and diminished microtubule-associated tubulins, as well as the severity of inflammation, demyelination, and axonal injury at the onset of optic neuritis.NeuroImage 06/2014; · 6.25 Impact Factor
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ABSTRACT: Axonal transport is critical for supplying newly synthesised proteins, organelles, mRNAs and other cargoes from neuronal cell bodies into axons. Its impairment in many neurodegenerative conditions appears likely to contribute to pathogenesis. Axonal transport also declines during normal ageing, but little is known about the timing of these changes, or about the effect of ageing on specific cargoes in individual axons. This is important for understanding mechanisms of age-related axon loss and age-related axonal disorders. Here we use fluorescence live-imaging of peripheral nerve and CNS tissue explants to investigate vesicular and mitochondrial axonal transport. Interestingly, we identify two distinct periods of change, one during young adulthood and one in old age, separated by a relatively stable plateau during most of adult life. We also find that after tibial nerve regeneration, even in old animals, neurons are able to support higher transport rates of each cargo for a prolonged period. Thus, the age-related decline in axonal transport is not an inevitable consequence of either ageing neurons or an ageing systemic milieu.Neurobiology of Aging. 09/2014;