New insights into the neuroprotective effects of anti-diabetic drugs using a mouse model of prion disease

Metabolic disorders like diabetes and obesity markedly elevate the risk of neurodegenerative diseases. While certain medications used to manage these conditions show neuroprotective potential, their exact mechanisms of action remain elusive. Here, we propose the utilization of brain histology in a mouse prion model as an effective approach for drug screening in dementia and for exploring the cellular mechanisms of neuroprotection offered by anti-diabetic drugs. Our primary objective was to establish the morphological criteria for brain pathology in prion-infected mice. To achieve this, C57BL/6J mice were injected with either RML scrapie-containing brain homogenate (RML) or normal brain homogenate (control). After 20 weeks, the animals were anesthetised, and their brains were isolated, fixed, and hippocampal coronal sections were subjected to H&E staining and immunohistochemistry (NeuN, p-PERK, GFAP, Iba1). Our findings revealed that RML mice exhibited significantly higher levels of spongiosis (number of holes in the brain parenchyma) and increased immunoreactivity of p-PERK (a cellular stress marker). Additionally, moderate astrocytosis was observed, along with dramatic changes in the number, soma area, and branching pattern of Iba1+ microglia in the CA1 area, compared to controls. We then aimed to assess the effectiveness of metformin, one of the most common anti-diabetic drugs, in mitigating the aforementioned pathological hallmarks. It was demonstrated that treatment with metformin decreased the level of spongiosis in the hippocampus. Furthermore, it alleviated brain microgliosis by reducing the number density and soma area of Iba1+ cells. Thus, anti-diabetic drugs may exert neuroprotective effects in prion disease through their anti-inflammatory properties.