Similar pattern of peripheral neuropathy in mouse models of type 1 diabetes and Alzheimer's disease

Abstract

There is an increasing awareness that diabetes has an impact on the CNS and that diabetes is a risk factor for Alzheimer's disease (AD). Links between AD and diabetes point to impaired insulin signaling as a common mechanism leading to defects in the brain. However, diabetes is predominantly characterized by peripheral, rather than central, neuropathy, and despite the common central mechanisms linking AD and diabetes, little is known about the effect of AD on the peripheral nervous system (PNS). In this study, we compared indexes of peripheral neuropathy and investigated insulin signaling in the sciatic nerve of insulin-deficient mice and amyloid precursor protein (APP) overexpressing transgenic mice. Insulin-deficient and APP transgenic mice displayed similar patterns of peripheral neuropathy with decreased motor nerve conduction velocity, thermal hypoalgesia, and loss of tactile sensitivity. Phosphorylation of the insulin receptor and glycogen synthase kinase 3β (GSK3β) was similarly affected in insulin-deficient and APP transgenic mice despite significantly different blood glucose and plasma insulin levels, and nerve of both models showed accumulation of Aβ-immunoreactive protein. Although diabetes and AD have different primary etiologies, both diseases share many abnormalities in both the brain and the PNS. Our data point to common deficits in the insulin-signaling pathway in both neurodegenerative diseases and support the idea that AD may cause disorders outside the higher CNS.

Figure 1

Motor nerve conduction velocity of the mouse sciatic nerve of 7-8 months old APP transgenic (APP) mice, or of age-matched mice after12 weeks of diabetes (STZ) compared to aged-matched wild type mice (WT). Data represent mean+SEM, N= 8 mice per WT and STZ groups, N=5 mice per APP group, *p<0.05 vs WT by one-way ANOVA followed by Dunnett’s post hoc test.

Figure 2

Paw thermal responses (A), IENF (B) and SNP profile (C) counts in 7-8 months old APP transgenic (APP) mice or in age-matched mice after12 weeks of diabetes (STZ) compared to aged-matched wild type mice (WT). Data represent mean+SEM, N= 8 mice per WT and STZ groups, N=5 mice per APP group, *p<0.05 vs WT by one-way ANOVA followed by Dunnett’s post hoc test.

Figure 3

PGP9.5-immunostained epidermal (arrows) and sub-epidermal (arrowheads) nerves fiber profiles in the skin of the hind paw of wild type (A), STZ (B) and APP transgenic (C) mice. Bar=40μm

Figure 4

Tactile responses of 7-8 months old APP transgenic (APP) mice or of age-matched mice after12 weeks of diabetes (STZ) compared to aged-matched wild type mice (WT). Data represent mean+SEM. N= 8 mice per WT and STZ groups, N=5 mice per APP group.

Figure 5

Phosphorylation of insulin receptor in mouse sciatic nerve. Scatter plot representing the individual ratio of intensity of pIR/actin (A) in mouse sciatic nerve of 7-8 months old APP transgenic (APP) mice, or of age-matched mice after 12 weeks of diabetes (STZ) compared to aged-matched wild type mice (WT). N=5 mice per group, *p<0.05 vs WT by one-way ANOVA followed by Dunnett’s post hoc test. Representative western blot of phosphorylated insulin receptor and actin (B) in mouse sciatic nerve of 7-8 months old APP transgenic (A) mice, or of age-matched mice after 12 weeks of diabetes (S) compared to aged-matched wild type mice (W).

Figure 6

Phosphorylation of GSK3β in mouse sciatic nerve. Scatter plot representing the individual ratio of intensity of pGSK3β/actin (A) in mouse sciatic nerve of 7-8 months old APP transgenic (APP) mice, or of age-matched mice after 12 weeks of diabetes (STZ) compared to aged-matched wild type mice (WT). N=5 mice per group, *p<0.05 vs WT by one-way ANOVA followed by Dunnett’s post hoc test. Representative western blot of phosphorylated GSK3β and actin (B) in mouse sciatic nerve of 7-8 months old APP transgenic (A) mice, or of age-matched mice after 12 weeks of diabetes (S) compared to aged-matched wild type mice (W).

Figure 7

Western blots and scatter plots representing the intensity of band corresponding to FL-APP (A) and amyloid β (16kDa, B) in the sciatic nerve of WT, STZ or APP transgenic mice, normalized against actin. N=5 mice per group, *p<0.05, **p< 0.01 vs WT by one-way ANOVA followed by Dunnett’s post hoc test.