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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- "2D and 3D). These differences highlight the advantages afforded by the acquisition of the long time-frame protocol we used, which gives access to all parameters of manganese transport (Cross et al., 2008). In contrast, short time-frame protocols are more widely used in mice, less time-consuming, and do not require any image registration; but they are limited to the analysis of an anatomical region predefined experimentally using a single parameter, the slope of manganese progression (Kim et al., 2011; Massaad et al., 2010; Smith et al., 2007, 2010a). "
ABSTRACT: The impairment of axonal transport by overexpression or hyperphosphorylation of tau is well documented for in vitro conditions; however, only a few studies on this phenomenon have been conducted in vivo, using invasive procedures, and with contradictory results. Here we used the non-invasive, Manganese-Enhanced Magnetic Resonance Imaging technique (MEMRI), to study for the first time a pure model of tauopathy, the JNPL3 transgenic mouse line, which overexpresses a mutated (P301L) form of the human tau protein. We show progressive impairment in neuronal transport as tauopathy advances. These findings are further supported by a significant correlation between the severity of the impairment in neuronal transport assessed by MEMRI, and the degree of abnormal tau assessed by histology. Unlike conventional techniques that focus on axonal transport measurement, MEMRI can provide a global analysis of neuronal transport, i.e. from dendrites to axons and at the macroscopic scale of fiber tracts. Neuronal transport impairment has been shown to be a key pathogenic process in Alzheimer's disease and numerous other neurodegenerative disorders. Hence, MEMRI provides a promising set of functional biomarkers to be used during preclinical trials to facilitate the selection of new drugs aimed at restoring neuronal transport in neurodegenerative diseases.NeuroImage 08/2012; 64(1). DOI:10.1016/j.neuroimage.2012.08.065 · 6.36 Impact Factor
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- "It is synthesized in nigral perikarya and transported to the synapse so quickly that it is undetectable in nigral cell bodies in young non-human primates and young humans (Chu and Kordower, 2007). In aged monkeys and aged humans, -synuclein can be detected, and this is a time in these primates' life where axonal transport defects have been noted (Li et al., 2004; Cross et al., 2008). Supported by the present data, it is therefore tempting to speculate that defects in axonal transport precede other changes leading to an accumulation of -synuclein within axon and perikarya. "
ABSTRACT: The progressive loss of the nigrostriatal pathway is a distinguishing feature of Parkinson's disease. As terminal field loss seems to precede cell body loss, we tested whether alterations of axonal transport motor proteins would be early features in Parkinson's disease. There was a decline in axonal transport motor proteins in sporadic Parkinson's disease that preceded other well-known nigral cell-related pathology such as phenotypic downregulation of dopamine. Reductions in conventional kinesin levels precede the alterations in dopaminergic phenotypic markers (tyrosine hydroxylase) in the early stages of Parkinson's disease. This reduction was significantly greater in nigral neurons containing α-synuclein inclusions. Unlike conventional kinesin, reductions in the levels of the cytoplasmic dynein light chain Tctex type 3 subunit were only observed at late Parkinson's disease stages. Reductions in levels of conventional kinesin and cytoplasmic dynein subunits were recapitulated in a rat genetic Parkinson's disease model based on over-expression of human mutant α-synuclein (A30P). Together, our data suggest that α-synuclein aggregation is a key feature associated with reductions of axonal transport motor proteins in Parkinson's disease and support the hypothesis that dopaminergic neurodegeneration following a 'dying-back' pattern involving axonal transport disruption.Brain 06/2012; 135(Pt 7):2058-73. DOI:10.1093/brain/aws133 · 10.23 Impact Factor
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- "Moreover, degradation of synaptic mitochondria is dependent on retrograde axonal transport due to the lack of lysosomes at synaptic ends (Hollenbeck, 1993; Tatsua and Langer, 2008). In agreement with previous reports (Cross et al., 2008; Hollenbeck and Saxton, 2005; Kimura et al., 2007), we did observe a significant age-related reduction in the level of the cytosolic protein kinesin, the main motor protein involved in anterograde mitochondrial axonal transport. Moreover, different studies have reported that retrograde axonal transport proteins are also affected during aging, as well as in neurodegenerative diseases, contributing to impaired retrograde transport of mitochondria and other organelles such as endosomes (Stokin and Goldstein, 2006; Kimura et al., 2009; Shi et al., 2010). "
ABSTRACT: Brain aging is associated with synaptic decline and synaptic function is highly dependent on mitochondria. Increased levels of oxidative DNA base damage and accumulation of mitochondrial DNA (mtDNA) mutations or deletions lead to mitochondrial dysfunction, playing an important role in the aging process and the pathogenesis of several neurodegenerative diseases. Here we have investigated the repair of oxidative base damage, in synaptosomes of mouse brain during normal aging and in an AD model. During normal aging, a reduction in the base excision repair (BER) capacity was observed in the synaptosomal fraction, which was associated with a decrease in the level of BER proteins. However, we did not observe changes between the synaptosomal BER activities of presymptomatic and symptomatic AD mice harboring mutated amyolid precursor protein (APP), Tau, and presinilin-1 (PS1) (3xTgAD). Our findings suggest that the age-related reduction in BER capacity in the synaptosomal fraction might contribute to mitochondrial and synaptic dysfunction during aging. The development of AD-like pathology in the 3xTgAD mouse model was, however, not associated with deficiencies of the BER mechanisms in the synaptosomal fraction when the whole brain was analyzed.Neurobiology of aging 04/2012; 33(4):694-707. DOI:10.1016/j.neurobiolaging.2010.06.019 · 4.85 Impact Factor