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Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy.

Simon CM, Rauskolb S, Gunnersen JM, Holtmann B, Drepper C, Dombert B, Braga M, Wiese S, Jablonka S, Pühringer D, Zielasek J, Hoeflich A, Silani V, Wolf E, Kneitz S, Sommer C, Toyka KV, Sendtner M - Acta Neuropathol. (2015)

Bottom Line: IGFBP5, an inhibitory binding protein for insulin-like growth factor 1 (IGF1) is highly up-regulated in nerve biopsies of patients with DNP.These data provide evidence that elevated expression of IGFBP5 in diabetic nerves reduces the availability of IGF1 for IGF1R on motor axons, thus leading to progressive neurodegeneration.Inhibition of IGFBP5 could thus offer novel treatment strategies for DNP.

View Article: PubMed Central - PubMed

Affiliation: Institute for Clinical Neurobiology, University of Würzburg, Versbacher-Str. 5, 97078, Würzburg, Germany.

ABSTRACT
Diabetic neuropathy (DNP), afflicting sensory and motor nerve fibers, is a major complication in diabetes. The underlying cellular mechanisms of axon degeneration are poorly understood. IGFBP5, an inhibitory binding protein for insulin-like growth factor 1 (IGF1) is highly up-regulated in nerve biopsies of patients with DNP. We investigated the pathogenic relevance of this finding in transgenic mice overexpressing IGFBP5 in motor axons and sensory nerve fibers. These mice develop motor axonopathy and sensory deficits similar to those seen in DNP. Motor axon degeneration was also observed in mice in which the IGF1 receptor (IGF1R) was conditionally depleted in motoneurons, indicating that reduced activity of IGF1 on IGF1R in motoneurons is responsible for the observed effect. These data provide evidence that elevated expression of IGFBP5 in diabetic nerves reduces the availability of IGF1 for IGF1R on motor axons, thus leading to progressive neurodegeneration. Inhibition of IGFBP5 could thus offer novel treatment strategies for DNP.

No MeSH data available.


Related in: MedlinePlus

Nerve fiber degeneration and spinal motoneuron loss are partly reflected in electrophysiological alterations in motor nerves of Igfbp5 transgenic mice. a Light micrographs of 6-month-old wild-type, Igfbp5 tg+ and cIgf1r ko phrenic nerve semithin sections stained with azur–methylene blue. Scale bar 20 µm. b, c Sciatic nerve cross sections of wild-type and Igfbp5 tg+ mice. No degenerating fibers were detectable in control tissue and small fibers appeared normal in Igfbp5 tg+ mice. Larger fibers of 6-month-old wild-type and Igfbp5 tg+ mice (arrows) showed signs of degeneration. Scale bar 10 μm. d Nissl-stained paraffin sections of the lumbar spinal cord showed degenerating motoneurons in Igfbp5 tg+ mice compared to wild-type animals. Scale bar 50 μm. e 3-week-old Igfbp5 tg+ mice showed a 15 % loss of phrenic nerve axons. f, g In 5- to 6-month-old Igfbp5 tg+ mice, the number of facial motoneurons was reduced by 17 %, and the number of lumbar spinal motoneurons by 20 %. h 9-Month-old Igfbp5 tg+ mice showed reduced grip strength compared with wild-type animals. i Motor nerve conduction velocity (M-NCV) was reduced significantly in Igfbp5 tg+ mice by 18 % in sciatic nerve. j Distal compound muscle action potential (CMAP) amplitudes were not altered in Igfbp5 tg+ and control animals. k Compound sensory–motor nerve conduction velocity (cSNCV) was not altered in Igfbp5 tg+ mice
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Fig6: Nerve fiber degeneration and spinal motoneuron loss are partly reflected in electrophysiological alterations in motor nerves of Igfbp5 transgenic mice. a Light micrographs of 6-month-old wild-type, Igfbp5 tg+ and cIgf1r ko phrenic nerve semithin sections stained with azur–methylene blue. Scale bar 20 µm. b, c Sciatic nerve cross sections of wild-type and Igfbp5 tg+ mice. No degenerating fibers were detectable in control tissue and small fibers appeared normal in Igfbp5 tg+ mice. Larger fibers of 6-month-old wild-type and Igfbp5 tg+ mice (arrows) showed signs of degeneration. Scale bar 10 μm. d Nissl-stained paraffin sections of the lumbar spinal cord showed degenerating motoneurons in Igfbp5 tg+ mice compared to wild-type animals. Scale bar 50 μm. e 3-week-old Igfbp5 tg+ mice showed a 15 % loss of phrenic nerve axons. f, g In 5- to 6-month-old Igfbp5 tg+ mice, the number of facial motoneurons was reduced by 17 %, and the number of lumbar spinal motoneurons by 20 %. h 9-Month-old Igfbp5 tg+ mice showed reduced grip strength compared with wild-type animals. i Motor nerve conduction velocity (M-NCV) was reduced significantly in Igfbp5 tg+ mice by 18 % in sciatic nerve. j Distal compound muscle action potential (CMAP) amplitudes were not altered in Igfbp5 tg+ and control animals. k Compound sensory–motor nerve conduction velocity (cSNCV) was not altered in Igfbp5 tg+ mice

Mentions: Next, we investigated the morphology of peripheral nerves. The number of sciatic nerve axons in Igfbp5 transgenic mice was reduced by 14 % when compared to wild-type animals at 6 months of age (P < 0.05, two-tailed Student’s t test) (Figs. 5e, 6b, c [arrows indicate degenerating axons], electronic supplementary Table A3). In parallel, a change in fiber size distribution in the sciatic nerve became apparent, with a significant reduction of fibers with a circumference between 20–25 µm in IGFBP5-overexpressing mice (P < 0.01, two-way ANOVA) (Fig. 5f). In addition, the M-ratio was significantly reduced by 20 % in transgenic animals (P < 0.05, two-tailed Student’s t test) (Fig. 5d, g). Quantification of myelinated axons in the phrenic nerve of 3-week-old Igfbp5 transgenic mice revealed a significant axonal loss of 15 % (P < 0.01, two-tailed Student’s t test) (Fig. 6e; electronic supplementary Table A3). No further loss of phrenic nerve fibers was detected in 5- to 6-month-old Igfbp5 transgenic mice (electronic supplementary Table A3; Fig. 6a). These data suggest that local inhibition of IGF1 not only affects motor axons but also the degree of myelination in Schwann cells. To determine whether axon degeneration and axon loss reflected loss of motoneuron cell bodies, we also counted motoneurons in the facial nucleus and the lumbar spinal cord of wild-type and Igfbp5 transgenic mice at different stages of postnatal development. In newborn and 3-week-old animals (Fig. 6f), numbers of facial motoneurons were not significantly different between wild-type and Igfbp5 transgenic mice (P > 0.05, one-way ANOVA) (electronic supplementary Table A3), indicating that neuronal IGFBP5 overexpression has no effect on the generation and developmental cell death of motoneurons. However, by 5–6 months of age, a 17 % loss of facial motoneurons became apparent (P < 0.01, one-way ANOVA) (Fig. 6f; electronic supplementary Table A3). In the spinal cord, no significant loss of motoneurons could be observed at 4 months of age (P > 0.05, one-way ANOVA). In contrast, at 5–6 months, a 20 % loss of motoneurons was observed (P < 0.001, one-way ANOVA) (Fig. 6g, electronic supplementary Table A3) and remaining spinal motoneurons exhibited signs of atrophy (Fig. 6d, indicated by white arrows). At 16 months, the level of motoneuron loss remained at 20 %, indicating that spinal motoneuron loss was maximal by 5–6 months and did not progress thereafter (P < 0.05, one-way ANOVA) (Fig. 6g; electronic supplementary Table A3). Nine-month-old Igfbp5 transgenic mice showed a significant reduction of forelimb grip strength (P < 0.001, one-way ANOVA) (Fig. 6h). In 5- to 6-month-old Igfbp5 transgenic mice, nerve conduction studies of the sciatic nerve [6, 29, 57] revealed that motor nerve conduction velocities (M-NCVs) were reduced by 18 % when compared to controls (P < 0.05; two-tailed Student’s t test) (Fig. 6i), which is compatible with a mild, putatively secondary demyelinating component of the neuropathy. Amplitudes of distal compound muscle action potentials (CMAPs) and compound sensory–motor nerve conduction velocities (cSNCVs) were not significantly altered (P > 0.05; two-tailed Student’s t test) (Fig. 6j, k; electronic supplementary Fig. A1).Fig. 6


Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy.

Simon CM, Rauskolb S, Gunnersen JM, Holtmann B, Drepper C, Dombert B, Braga M, Wiese S, Jablonka S, Pühringer D, Zielasek J, Hoeflich A, Silani V, Wolf E, Kneitz S, Sommer C, Toyka KV, Sendtner M - Acta Neuropathol. (2015)

Nerve fiber degeneration and spinal motoneuron loss are partly reflected in electrophysiological alterations in motor nerves of Igfbp5 transgenic mice. a Light micrographs of 6-month-old wild-type, Igfbp5 tg+ and cIgf1r ko phrenic nerve semithin sections stained with azur–methylene blue. Scale bar 20 µm. b, c Sciatic nerve cross sections of wild-type and Igfbp5 tg+ mice. No degenerating fibers were detectable in control tissue and small fibers appeared normal in Igfbp5 tg+ mice. Larger fibers of 6-month-old wild-type and Igfbp5 tg+ mice (arrows) showed signs of degeneration. Scale bar 10 μm. d Nissl-stained paraffin sections of the lumbar spinal cord showed degenerating motoneurons in Igfbp5 tg+ mice compared to wild-type animals. Scale bar 50 μm. e 3-week-old Igfbp5 tg+ mice showed a 15 % loss of phrenic nerve axons. f, g In 5- to 6-month-old Igfbp5 tg+ mice, the number of facial motoneurons was reduced by 17 %, and the number of lumbar spinal motoneurons by 20 %. h 9-Month-old Igfbp5 tg+ mice showed reduced grip strength compared with wild-type animals. i Motor nerve conduction velocity (M-NCV) was reduced significantly in Igfbp5 tg+ mice by 18 % in sciatic nerve. j Distal compound muscle action potential (CMAP) amplitudes were not altered in Igfbp5 tg+ and control animals. k Compound sensory–motor nerve conduction velocity (cSNCV) was not altered in Igfbp5 tg+ mice
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Fig6: Nerve fiber degeneration and spinal motoneuron loss are partly reflected in electrophysiological alterations in motor nerves of Igfbp5 transgenic mice. a Light micrographs of 6-month-old wild-type, Igfbp5 tg+ and cIgf1r ko phrenic nerve semithin sections stained with azur–methylene blue. Scale bar 20 µm. b, c Sciatic nerve cross sections of wild-type and Igfbp5 tg+ mice. No degenerating fibers were detectable in control tissue and small fibers appeared normal in Igfbp5 tg+ mice. Larger fibers of 6-month-old wild-type and Igfbp5 tg+ mice (arrows) showed signs of degeneration. Scale bar 10 μm. d Nissl-stained paraffin sections of the lumbar spinal cord showed degenerating motoneurons in Igfbp5 tg+ mice compared to wild-type animals. Scale bar 50 μm. e 3-week-old Igfbp5 tg+ mice showed a 15 % loss of phrenic nerve axons. f, g In 5- to 6-month-old Igfbp5 tg+ mice, the number of facial motoneurons was reduced by 17 %, and the number of lumbar spinal motoneurons by 20 %. h 9-Month-old Igfbp5 tg+ mice showed reduced grip strength compared with wild-type animals. i Motor nerve conduction velocity (M-NCV) was reduced significantly in Igfbp5 tg+ mice by 18 % in sciatic nerve. j Distal compound muscle action potential (CMAP) amplitudes were not altered in Igfbp5 tg+ and control animals. k Compound sensory–motor nerve conduction velocity (cSNCV) was not altered in Igfbp5 tg+ mice
Mentions: Next, we investigated the morphology of peripheral nerves. The number of sciatic nerve axons in Igfbp5 transgenic mice was reduced by 14 % when compared to wild-type animals at 6 months of age (P < 0.05, two-tailed Student’s t test) (Figs. 5e, 6b, c [arrows indicate degenerating axons], electronic supplementary Table A3). In parallel, a change in fiber size distribution in the sciatic nerve became apparent, with a significant reduction of fibers with a circumference between 20–25 µm in IGFBP5-overexpressing mice (P < 0.01, two-way ANOVA) (Fig. 5f). In addition, the M-ratio was significantly reduced by 20 % in transgenic animals (P < 0.05, two-tailed Student’s t test) (Fig. 5d, g). Quantification of myelinated axons in the phrenic nerve of 3-week-old Igfbp5 transgenic mice revealed a significant axonal loss of 15 % (P < 0.01, two-tailed Student’s t test) (Fig. 6e; electronic supplementary Table A3). No further loss of phrenic nerve fibers was detected in 5- to 6-month-old Igfbp5 transgenic mice (electronic supplementary Table A3; Fig. 6a). These data suggest that local inhibition of IGF1 not only affects motor axons but also the degree of myelination in Schwann cells. To determine whether axon degeneration and axon loss reflected loss of motoneuron cell bodies, we also counted motoneurons in the facial nucleus and the lumbar spinal cord of wild-type and Igfbp5 transgenic mice at different stages of postnatal development. In newborn and 3-week-old animals (Fig. 6f), numbers of facial motoneurons were not significantly different between wild-type and Igfbp5 transgenic mice (P > 0.05, one-way ANOVA) (electronic supplementary Table A3), indicating that neuronal IGFBP5 overexpression has no effect on the generation and developmental cell death of motoneurons. However, by 5–6 months of age, a 17 % loss of facial motoneurons became apparent (P < 0.01, one-way ANOVA) (Fig. 6f; electronic supplementary Table A3). In the spinal cord, no significant loss of motoneurons could be observed at 4 months of age (P > 0.05, one-way ANOVA). In contrast, at 5–6 months, a 20 % loss of motoneurons was observed (P < 0.001, one-way ANOVA) (Fig. 6g, electronic supplementary Table A3) and remaining spinal motoneurons exhibited signs of atrophy (Fig. 6d, indicated by white arrows). At 16 months, the level of motoneuron loss remained at 20 %, indicating that spinal motoneuron loss was maximal by 5–6 months and did not progress thereafter (P < 0.05, one-way ANOVA) (Fig. 6g; electronic supplementary Table A3). Nine-month-old Igfbp5 transgenic mice showed a significant reduction of forelimb grip strength (P < 0.001, one-way ANOVA) (Fig. 6h). In 5- to 6-month-old Igfbp5 transgenic mice, nerve conduction studies of the sciatic nerve [6, 29, 57] revealed that motor nerve conduction velocities (M-NCVs) were reduced by 18 % when compared to controls (P < 0.05; two-tailed Student’s t test) (Fig. 6i), which is compatible with a mild, putatively secondary demyelinating component of the neuropathy. Amplitudes of distal compound muscle action potentials (CMAPs) and compound sensory–motor nerve conduction velocities (cSNCVs) were not significantly altered (P > 0.05; two-tailed Student’s t test) (Fig. 6j, k; electronic supplementary Fig. A1).Fig. 6

Bottom Line: IGFBP5, an inhibitory binding protein for insulin-like growth factor 1 (IGF1) is highly up-regulated in nerve biopsies of patients with DNP.These data provide evidence that elevated expression of IGFBP5 in diabetic nerves reduces the availability of IGF1 for IGF1R on motor axons, thus leading to progressive neurodegeneration.Inhibition of IGFBP5 could thus offer novel treatment strategies for DNP.

View Article: PubMed Central - PubMed

Affiliation: Institute for Clinical Neurobiology, University of Würzburg, Versbacher-Str. 5, 97078, Würzburg, Germany.

ABSTRACT
Diabetic neuropathy (DNP), afflicting sensory and motor nerve fibers, is a major complication in diabetes. The underlying cellular mechanisms of axon degeneration are poorly understood. IGFBP5, an inhibitory binding protein for insulin-like growth factor 1 (IGF1) is highly up-regulated in nerve biopsies of patients with DNP. We investigated the pathogenic relevance of this finding in transgenic mice overexpressing IGFBP5 in motor axons and sensory nerve fibers. These mice develop motor axonopathy and sensory deficits similar to those seen in DNP. Motor axon degeneration was also observed in mice in which the IGF1 receptor (IGF1R) was conditionally depleted in motoneurons, indicating that reduced activity of IGF1 on IGF1R in motoneurons is responsible for the observed effect. These data provide evidence that elevated expression of IGFBP5 in diabetic nerves reduces the availability of IGF1 for IGF1R on motor axons, thus leading to progressive neurodegeneration. Inhibition of IGFBP5 could thus offer novel treatment strategies for DNP.

No MeSH data available.


Related in: MedlinePlus