A regional and cellular analysis of the early intracellular and extracellular accumulation of Aβ in the brain of 5XFAD mice

Intracellular A beta (iA beta) expression, extracellular A beta (eA beta) plaque formation and microglial reactivity are characteristic neuropathological events of Alzheimer?s disease (AD) and have been detected in several transgenic mouse models of this disease. In this work we decided to investigate the early (2?7 months of age) development of these phenomena at both regional and cellular levels in 5XFAD mice, a severe transgenic mouse model of AD. We demonstrated that 1) A beta pathology develops in many but not all brain regions, 2) iA beta is transient and almost always followed by eA beta in grey matter regions, and the respective levels are roughly proportional, and 3) in about 1/3 of the grey matter regions with A beta pathology and in several white matter regions, eA beta plaques can appear where no iA beta-positive structures were detected. We also showed that male and female mice share a similar regional and cellular pattern of A beta pathology development that is more prominent in females. Early iA beta is associated to the activation of microglia, while subsequent formation of eA beta plaques is associated with markedly increased density of microglial cells that acquire a characteristic clustered phenotype. Present analysis is relevant to set a reference for pathophysiological studies and to define specific targets for the test of therapeutic interventions in this widely used AD transgenic model.

Automated summary

This study investigated the early development of A beta pathology in 5XFAD mice, a severe transgenic mouse model of AD, and found that A beta pathology develops in many brain regions, with iA beta being transient and followed by eA beta in grey matter regions. The activation of microglia is associated with early iA beta, while the subsequent formation of eA beta plaques is associated with increased density of microglial cells.