Skin capillary amylin deposition resembles brain amylin vasculopathy in rats

Background and purpose: Human amylin is a 37 amino-acid pancreatic peptide that forms neuro-toxic aggregates that deposit in the endothelium of brain capillaries of patients with diabetes, potentially contributing to cerebral small vessel ischemic injury. Pathogenic amylin also deposits in the capillary endothelium in other organs, including the skin. The aim of this study was to test the hypothesis that skin capillary amylin deposition correlates with cerebral small vessel amylin deposition, potentially providing a clinically useful marker of cerebral amylin deposition.Methods: Immunohistochemistry (IHC) was performed for human amylin and collagen IV in brain and skin sections of rats (age 15-16 months) with pancreatic overexpression of amyloidogenic human amylin polypeptide (HIP rats), and control rats (Wild type; WT; rats that express non-amyloidogenic rat amylin) using antibodies binding amylin (n = 5 male and 5 female rats for each group) and antibodies binding Hypoxia inducing factor (HIF)-1 & alpha; and HIF-2 & alpha; (n = 3 for each group). The reactive amylin-aldehyde 4-hydroxynonenal (4-HNE) adduct was measured in skin homogenates. (n = 4 for each group) Results: Brain capillaries isolated from HIP rats had higher amylin content compared to WT rats using Western blot with anti-amylin antibody (p = 0.0010). The HIF-1 & alpha; and HIF-2 & alpha; immunoreactivity signals in skin from HIP and WT rats were similar (p = 0.2 for HIF-1 & alpha;, and p = 0.75 for HIF-2 & alpha;). Amylin-4HNE adduct formation was higher in HIP rats compared to WT rats (p = 0.0014). There was phenotypic similarity between brain and skin capillary amylin based on co-staining for human amylin and collagen IV in both HIP and WT rats. Conclusion: Skin and brain capillary amylin deposition are similar providing evidence that a skin biopsy might be providing a potential biomarker for diabetes-associated intracranial vasculopathy.