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Axonal transport declines with age in two distinct phases separated by a period of relative stability.

Milde S, Adalbert R, Elaman MH, Coleman MP - Neurobiol. Aging (2014)

Bottom Line: Axonal transport also declines during normal aging, but little is known about the timing of these changes, or about the effect of aging on specific cargoes in individual axons.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 aging neurons or an aging systemic milieu.

View Article: PubMed Central - PubMed

Affiliation: Signalling ISP, The Babraham Institute, Babraham Research Campus, Cambridge, UK.

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Age-associated changes in mitochondrial transport in sciatic nerve axons. (A) Representative straightened axon, kymograph, and kymograph of tracked particles of mitochondrial transport in sciatic nerves of 3- and 12-month-old MitoS mice. The straightened axon represents the first frame of the time lapse recording (total 360 frames; frame rate 2 fps) that was used to generate the original kymograph. Moving particles were tracked using the ImageJ Difference Tracker set of plugins (see Table 2 for analysis parameters) and another kymograph generated to show successfully tracked particles. (B–E) Quantification of axonal transport parameters in sciatic nerve explants from MitoS animals of indicated ages. For all graphs, each data point represents the mean value obtained for 1 animal (5 fields of view and, on average, 19 axons per animal). Horizontal bar indicates mean and error bars standard error of the mean. Statistically significant differences between ages or groups of ages are indicated as follows: ∗∗ p < 0.01; ∗∗∗p < 0.001 (Student t test). The following parameters are shown: (B) anterograde particle count, (C) retrograde particle count, (D) anterograde particle velocity, and (E) retrograde particle velocity. (For interpretation of the references to color in this Figure, the reader is referred to the web version of this article.)
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fig2: Age-associated changes in mitochondrial transport in sciatic nerve axons. (A) Representative straightened axon, kymograph, and kymograph of tracked particles of mitochondrial transport in sciatic nerves of 3- and 12-month-old MitoS mice. The straightened axon represents the first frame of the time lapse recording (total 360 frames; frame rate 2 fps) that was used to generate the original kymograph. Moving particles were tracked using the ImageJ Difference Tracker set of plugins (see Table 2 for analysis parameters) and another kymograph generated to show successfully tracked particles. (B–E) Quantification of axonal transport parameters in sciatic nerve explants from MitoS animals of indicated ages. For all graphs, each data point represents the mean value obtained for 1 animal (5 fields of view and, on average, 19 axons per animal). Horizontal bar indicates mean and error bars standard error of the mean. Statistically significant differences between ages or groups of ages are indicated as follows: ∗∗ p < 0.01; ∗∗∗p < 0.001 (Student t test). The following parameters are shown: (B) anterograde particle count, (C) retrograde particle count, (D) anterograde particle velocity, and (E) retrograde particle velocity. (For interpretation of the references to color in this Figure, the reader is referred to the web version of this article.)

Mentions: The significant drop in transport rates of NMNAT2-Venus particles observed from 3 to 6 months of age prompted us to ask whether this was a general effect on multiple fast axonal transport cargoes, or perhaps a more specific effect on NMNAT2 vesicles. To start addressing this question, we imaged mitochondrial transport in sciatic nerves of MitoS mice expressing mitochondrially targeted CFP under the same Thy1.2 promoter (Fig 2A). We previously reported a fall in axonal transport in these mice between 8 and 24 months (Gilley et al., 2012), but earlier ages have not been studied. Here, we observed a significant drop in the number of anterogradely and retrogradely transported mitochondria from 3 to 6 months of age, with no further change until at least 12 months (Fig 2B and C). Over the same time course, no significant changes in transport velocities were observed (Fig 2D and E). As for NMNAT2-Venus above, changes in the average fluorescence intensity of labeled axons are unlikely to account for these differences (Table 3). These findings parallel the results for NMNAT2-Venus above and suggest a general reduction in fast axonal transport rates in peripheral nerves between 3 and 6 months of age, followed by a more stable plateau during adult life. Combined with our findings in older MitoS mice (Gilley et al., 2012), these results suggest 2 major periods of reduction in the fast axonal transport of several cargoes, 1 occurring in young animals between 3 and 6 months of age, and the other during old age after 18 months.


Axonal transport declines with age in two distinct phases separated by a period of relative stability.

Milde S, Adalbert R, Elaman MH, Coleman MP - Neurobiol. Aging (2014)

Age-associated changes in mitochondrial transport in sciatic nerve axons. (A) Representative straightened axon, kymograph, and kymograph of tracked particles of mitochondrial transport in sciatic nerves of 3- and 12-month-old MitoS mice. The straightened axon represents the first frame of the time lapse recording (total 360 frames; frame rate 2 fps) that was used to generate the original kymograph. Moving particles were tracked using the ImageJ Difference Tracker set of plugins (see Table 2 for analysis parameters) and another kymograph generated to show successfully tracked particles. (B–E) Quantification of axonal transport parameters in sciatic nerve explants from MitoS animals of indicated ages. For all graphs, each data point represents the mean value obtained for 1 animal (5 fields of view and, on average, 19 axons per animal). Horizontal bar indicates mean and error bars standard error of the mean. Statistically significant differences between ages or groups of ages are indicated as follows: ∗∗ p < 0.01; ∗∗∗p < 0.001 (Student t test). The following parameters are shown: (B) anterograde particle count, (C) retrograde particle count, (D) anterograde particle velocity, and (E) retrograde particle velocity. (For interpretation of the references to color in this Figure, the reader is referred to the web version of this article.)
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Related In: Results  -  Collection

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Show All Figures
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fig2: Age-associated changes in mitochondrial transport in sciatic nerve axons. (A) Representative straightened axon, kymograph, and kymograph of tracked particles of mitochondrial transport in sciatic nerves of 3- and 12-month-old MitoS mice. The straightened axon represents the first frame of the time lapse recording (total 360 frames; frame rate 2 fps) that was used to generate the original kymograph. Moving particles were tracked using the ImageJ Difference Tracker set of plugins (see Table 2 for analysis parameters) and another kymograph generated to show successfully tracked particles. (B–E) Quantification of axonal transport parameters in sciatic nerve explants from MitoS animals of indicated ages. For all graphs, each data point represents the mean value obtained for 1 animal (5 fields of view and, on average, 19 axons per animal). Horizontal bar indicates mean and error bars standard error of the mean. Statistically significant differences between ages or groups of ages are indicated as follows: ∗∗ p < 0.01; ∗∗∗p < 0.001 (Student t test). The following parameters are shown: (B) anterograde particle count, (C) retrograde particle count, (D) anterograde particle velocity, and (E) retrograde particle velocity. (For interpretation of the references to color in this Figure, the reader is referred to the web version of this article.)
Mentions: The significant drop in transport rates of NMNAT2-Venus particles observed from 3 to 6 months of age prompted us to ask whether this was a general effect on multiple fast axonal transport cargoes, or perhaps a more specific effect on NMNAT2 vesicles. To start addressing this question, we imaged mitochondrial transport in sciatic nerves of MitoS mice expressing mitochondrially targeted CFP under the same Thy1.2 promoter (Fig 2A). We previously reported a fall in axonal transport in these mice between 8 and 24 months (Gilley et al., 2012), but earlier ages have not been studied. Here, we observed a significant drop in the number of anterogradely and retrogradely transported mitochondria from 3 to 6 months of age, with no further change until at least 12 months (Fig 2B and C). Over the same time course, no significant changes in transport velocities were observed (Fig 2D and E). As for NMNAT2-Venus above, changes in the average fluorescence intensity of labeled axons are unlikely to account for these differences (Table 3). These findings parallel the results for NMNAT2-Venus above and suggest a general reduction in fast axonal transport rates in peripheral nerves between 3 and 6 months of age, followed by a more stable plateau during adult life. Combined with our findings in older MitoS mice (Gilley et al., 2012), these results suggest 2 major periods of reduction in the fast axonal transport of several cargoes, 1 occurring in young animals between 3 and 6 months of age, and the other during old age after 18 months.

Bottom Line: Axonal transport also declines during normal aging, but little is known about the timing of these changes, or about the effect of aging on specific cargoes in individual axons.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 aging neurons or an aging systemic milieu.

View Article: PubMed Central - PubMed

Affiliation: Signalling ISP, The Babraham Institute, Babraham Research Campus, Cambridge, UK.

Show MeSH
Related in: MedlinePlus