AMYLIN DYSHOMEOSTASIS: A NON-AD PROCESS CONTRIBUTING TO AN AD PHENOTYPE

Abstract

Recent studies from several laboratories showed that amylin, an amyloidogenic peptide that kills the pancreatic β-cells in patients with type-2 diabetes, forms neuritic deposits and mixed amylin-Aβ plaques in brains of individuals with AD. Here, we tested the hypothesis that systemic amylin dyshomeostasis accelerates the development of AD. TgF344-19 AD rats (which overexpress human APPSwe/PS1DE9 from a PrP promoter) were crossed with rats expressing human amylin in the pancreas (HIP rats). The newly generated ADHIP rats were compared with HIP, AD and wild-type (WT) littermates (males; n=10/group) by Morris Water Maze (MWM). MWM tests were performed at 12 months of age (when HIP rats develop amylin pathology) and 16 months of age (when AD rats have fully developed AD-like pathology). Brain structure in each rat was assessed by T2-weighted MRI (7T; TR: 3000ms; TE: 24ms). At 12 and 16 months of age, n=5 animals from each group were investigated for cellular markers of the blood-brain barrier (BBB) injury and interaction of amylin with Aβ. Amylin dyshomeostasis greatly accelerated brain structural abnormalities in ADHIP rats, as demonstrated by enlarged ventricles and brain atrophy. Compared to WT controls, ADHIP, AD and HIP rats have impaired learning (P<0.05). The latency to platform is significantly longer for ADHIP rats compared to AD rats (P=0.03) indicating a faster decline of brain function in ADHIP rats.Staining of brain sections using cellular markers of astrocytes (GFAP), microglia/macrophages (CD11b), microglia (Iba1), reactive microglia (CD68), and select microglial phenotype markers (IL-1b and TNFa as M1 markers; Arg1 and CD36 as M2 markers) demonstrates BBB breakdown in ADHIP and HIP rats. Cerebral vascular amylin deposits, microhemorrhages, loss of endothelial cell coverage in capillaries and white matter rarefaction were also seen in ADHIP and HIP, but not AD and WT rats. At 16 months of age, the latency to platform was similar for ADHIP and AD rats. Histologic analysis revealed mixed Aβ-amylin plaques in brains of ADHIP rats. Systemic amylin dyshomeostasis and subsequent accumulation of oligomerized amylin in the brain greatly accelerates AD-like pathology by provoking BBB breakdown and Aβ-amylin deposition in the brain parenchyma.