Spatiotemporal development of the neuronal accumulation of amyloid precursor protein and the amyloid plaque formation in the brain of 3xTg-AD mice

The amyloid plaque is a hallmark of Alzheimer's disease. The accumulation of the amyloid precursor protein (APP) in the neuronal structure is assumed to lead to amyloid plaque formation through the excessive production of β-amyloid protein. To study the relationship between the neuronal accumulation of APP and amyloid plaque formation, we histologically analyzed their development in the different brain regions in 3xTg-AD mice, which express Swedish mutated APP (APP_SWE) in the neurons. Observation throughout the brain revealed APP_SWE-positive somata in the broad regions. Quantitative model analysis showed that the somatic accumulation of APP_SWE developed firstly in the hippocampus from a very early age (<1 month) and proceeded slower in the isocortex. In line with this, the hippocampus was the first region to form amyloid plaques at the age of 9–12 months, while amyloid plaques were rarely observed in the isocortex. Females had more APP_SWE-positive somata and plaques than males. Furthermore, amyloid plaques were observed in the lateral septum and pontine grey, which did not contain APP_SWE-positive somata but only the APP_SWE-positive fibers. These results suggested that neuronal accumulation of APP_SWE, both in somatodendritic and axonal domains, is closely related to the formation of amyloid plaques.