Increases in Neuroinflammation and Astrocyte Activation in a Murine Model of Mixed Dementia

Abstract

Obesity and type 2 diabetes mellitus are risk factors for developing Alzheimer's disease (AD) and vascular dementia. This disease pathology includes small strokes, cerebrovascular occlusions, and cerebral microhemorrhages. To examine this unique disease state we developed a db/AD mouse model: a cross between the db/db diabetic mouse and the APP(ΔNL)/PS1(P264L) double knock‐in model of amyloid pathology. The diabetic phenotype causes unique vascular changes, including aneurysms, microhemorrhages, and microinfarcts. Gene expression profiles were collected using microarray data analysis and array cards probing for neuroinflammatory markers. Microglial activation, astrocytic dysfunction, and neurovascular coupling were assessed via immunohistochemistry. The db/AD mice had significant differences in metabolic pathways and a general increase in neuroinflammation, including astrocyte and microglial activation. Additionally, we saw changes in the aquaporin‐4 water channel, the calcium‐dependent potassium channel Kir4.1, and several matrix metalloproteinases, indicating astrocyte dysfunction. We have created a mouse that models a mixed dementia disease state that can be used to better understand how obesity and type 2 diabetes contribute to the development of dementia. Further elucidating the roles of inflammation and astrocyte activation in the development of pathology will be important for improving our understanding of the disease, and for the design of potential therapies. Funded by NIH (ES024158, AG045809, NS083692).