Comparison of microglial cell population expansion in the Tg344-AD rat and APPSWE/PS1ΔE9 mouse model of Alzheimer's disease.

Background: Chronic microglial activation is a key characteristic of Alzheimer's disease (AD). In mouse models of AD, microglial activation is considered associated with microglial cell population expansion. Objective: To elucidate species- and gene-dosage-dependent differences and similarities in microglial cell population expansion in response to amyloid-β (Aβ) plaque pathology. Methods: The total number of Iba1+ microglia in the neocortex of hemizygous APPswe/PS1ΔE9 (APP/PS1) mice and hemi- and homozygous TgF344-AD rats, carrying the same human mutations, was estimated by use of stereological techniques. Furthermore, microglial cluster formation was assessed. Proliferation was assessed in the mouse model. Results: A significant two-fold increase in microglia was observed in the neocortex of hemizygous APP/PS1 mice at 18 months and of homozygous TgF344-AD rats at 17 months. In comparison, the number of microglia in hemizygous TgF344-AD rats, remained constant from 4 to 17 months. Microglial clusters formed prior to the increase in microglial numbers in both species. The clusters were typically small, surrounding the smaller-sized Aβ plaques, occasionally also containing recently proliferated microglia. The Aβ plaque loads were comparable in hemizygous TgF344-AD rats and APP/PS1 mice, and two-three-fold higher in homozygous TgF344-AD rats. The microglial population remained constant across ages in wild types in both species. Conclusions: Transgenic mouse and rat AD models show significant differences in microglial population expansion, with a more restrained expansion in the rat. However, in both species and regardless of gene-dosage, population expansion is preceded by microglial clustering around Aβ plaques, indicating that cluster-formation is a key event in AD neuropathology.