The accumulation of the amyloid-beta peptide (Abeta) in the brain is considered to have a primary role in Alzheimer's disease (AD). In addition to the extracellular accumulation of Abeta in the parenchyma and cerebrovasculature, emerging evidence indicates that intraneuronal Abeta also plays a pathophysiological role in AD. It is unclear, however, if the intracellular and extracellular pools of Abeta are unrelated or connected. In these studies, we sought to establish a relationship between these two pools of Abeta. We identified an inverse relationship between intracellular and extracellular Abeta in the 3xTg-AD transgenic model of AD. Using an immunotherapy approach, we further found that extracellular Abeta was cleared before intracellular Abeta. After the antibody dissipated, however, the reappearance of extracellular plaques was preceded by the accumulation of intraneuronal Abeta. Taken together, these results provide strong experimental evidence that intraneuronal Abeta may serve as a source for some of the extracellular amyloid deposits.