Diet‐induced insulin resistance elevates hippocampal glutamate as well as VGLUT1 and GFAP expression in AβPP/PS1 mice

The symptomologies of Alzheimer's disease (AD) develop over decades suggesting modifiable lifestyle factors may contribute to disease pathogenesis. In humans, hyperinsulinemia associated with type 2 diabetes mellitus increases the risk for developing AD and both diseases share similar age‐related etiologies including amyloidogenesis. Since we have demonstrated that soluble Aβ42 elicits glutamate release, we wanted to understand how diet‐induced insulin resistance alters hippocampal glutamate dynamics, which are important for memory formation and consolidation. Eight to twelve‐week‐old C57BL/6J and AβPP/PS1 mice were placed on either a low‐fat diet or high‐fat diet (HFD) for 8 months. A HFD led to significant weight increases as well as impaired insulin sensitivity, glucose tolerance, and learning in both C57BL/6J and AβPP/PS1 mice. AβPP/PS1 low‐fat diet mice had elevated hippocampal basal as well as stimulus‐evoked glutamate release that was further increased with consumption of a HFD. Immunohistochemistry indicated an increase in vesicular glutamate transporter 1 and glial fibrillary acidic protein density in hippocampal subregions corresponding with this elevated extracellular glutamate. While no differences in hippocampal plaque load were observed, the elevated astrogliotic response surrounding the plaques in AβPP/PS1 HFD mice may have been a compensatory mechanism to control plaque accumulation. These data support that AβPP/PS1 mice have chronically elevated extracellular glutamate that is exacerbated by a HFD and that modifiable lifestyle factors such as obesity‐induced insulin resistance can contribute to AD pathogenesis. Open science badges This article has received a badge for *Open Materials* and for *Open Data* because it made the data publicly available. The data can be accessed at https://osf.io/5whvu (figures for data) and https://osf.io/gd5vf (materials and methods). The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/. Cover Image for this issue: doi: 10.1111/jnc.14490. The aim of the present study was to address how obesity‐induced insulin resistance alters hippocampal glutamate dynamics in both cognitively normal and AβPP/PS1 mice predisposed to Alzheimer's disease (AD) pathology. AβPP/PS1 mice presented with insulin resistance, neuroinflammation, and elevated hippocampal glutamate