Cerebrovascular accumulation of amyloid-forming amylin secreted from the pancreas induces brain hypoxia

Abstract

Background

Islet amyloid polypeptide (amylin) is a β-cell hormone co-secreted with insulin. Histological analyses of human brains identified amylin deposits co-localized with parenchymal and vascular β-amyloid in humans with vascular cognitive impairment and Alzheimer’s dementia. Because circulating amyloid-forming amylin triggers systemic hypoxia signaling, we sought to determine the relationship between circulating amylin levels and brain hypoxia markers in a transgenic rat model of amylin-mediated neurological deficits.

Method

To assess amylin-related brain hypoxia signaling, we performed a 16-month longitudinal study in which rats that express amyloid-forming human amylin in pancreatic β-cells (HIP rats) were compared to wild type (WT) littermates that express non-amyloidogenic rodent amylin (n=10 rats/group).

Result

Blood amylin levels measured by ELISA were ∼2-fold higher in 16-month old HIP rats compared to WT littermates (P<0.01). The Thiovlavin T (Th T) fluorescence signal intensity in blood lysates from HIP rats increased compared to that in WT littermates indicating the presence of amyloid-forming in the circulation in HIP rats (P<0.01). This was associated with higher amylin concentration in brain microvessel lysates (P<0.05) and amylin immunoreactivity signal intensity in brain sections. Plasma erythropoietin, a marker of systemic hypoxia was higher in HIP rats than in WT littermates (P<0.05), which correlated with brain accumulation of HIF-2α (P<0.05) and HIF-1α (P=0.07), and with altered mitochondrial DNA in brain tissue (P<0.05).

Conclusion

Increased circulating levels of amyloid-forming amylin promotes cerebrovascular amylin deposition leading to brain hypoxic-ischemic injury. Future studies need to address functional effects of amylin-induced brain hypoxia signaling in the brain.