In vivo downregulation of pancreatic amylin improves brain function and reduces brain β amyloid pathology in APP/PS1 mice

Abstract

AbstractBackgroundAmylin is a systemic hormone that is co‐secreted with insulin from pancreatic β‐cells. Amylin co‐aggregates with brain parenchymal and vascular b‐amyloid in persons with Alzheimer’s dementia. Cross‐sectional data show higher CSF and blood amylin levels are associated with increased frequency of cognitive impairment. The present study sought to determine how in vivo downregulation of amylin influences brain function during the development of Aβ pathology.MethodBecause mouse amylin is nonamyloidogenic, we developed an APP/PS1 mouse model in which the mouse amylin gene is replaced by the human amylin gene and is conditionally regulated by tamoxifen (TMX) injection, intraperitonially. At 3 months of age, human amylin‐expressing male mice were randomly assigned to either amylin downregulation group or control group (maintained amylin expression) (n = 10/group). Two months later, we assessed brain function with the novel object recognition test and performed comparative immunochemical Aβ analyses of hippocampal tissue by using MSD ELISA and immunohistochemistry (IHC).ResultMice with downregulated human amylin show enhanced recognition memory index (p < 0.001) and lower plasma amylin levels (p < 0.001) compared to those that continued to express human amylin. This was associated with decreased hippocampal levels of Aβ42 (p < 0.05) measured by MSD ELISA and decreased number of plaques (P < 0.01) measured by IHC.ConclusionAmylin downregulation in APP/PS1 mice improves memory. Molecular processes associated with improved memory involve decreased hippocampal Aβ pathology. Further studies are needed to understand how altered secretion of pancreatic amylin may influences the balance between brain Aβ accumulation and Aβ elimination from the brain.