Pigmented and Dunkin‐Hartley Guinea Pigs as Natural Models for Brain Aging and Alzheimer’s Disease

Abstract

Aging is the primary risk factor for most chronic diseases, including Alzheimer’s disease (AD). Current pre‐clinical approaches for studying brain aging and AD rely primarily on transgenic models intended to mirror pathologies associated with human brain aging and neurodegeneration (e.g., by increasing production of amyloid beta (Aβ) and phosphorylated tau). While these models may be useful, none completely mimic AD and its strong age‐dependence, and there has been limited success in translating pre‐clinical results and treatments to humans. We have characterized two non‐transgenic guinea pig strains (common ‘Pigmented’ guinea pigs and the Dunkin‐Hartley strain) that may be more useful models of brain aging and AD in this context. We show that these two models share many transcriptome features with both human brain aging and age‐related AD, especially with respect to biological processes like inflammation and transcriptional dysregulation. Additionally, both Pigmented and Dunkin‐Hartley animals exhibit age‐associated increases in numerous markers of human brain aging/AD, including neurofilament light chain (NfL, a marker of neuronal damage), S100 calcium‐binding protein B (S100ß, a marker of glial activation), ionized calcium‐binding adapter molecule 1 (Iba1, a marker of reactive microglia), and both Aβ and phosphorylated tau. These age‐associated effects are generally stronger in Dunkin‐Hartley animals, suggesting that this strain may be useful to model AD, while the Pigmented strain may be useful to model normal human brain aging.