A dynamic relationship between intracellular and extracellular pools of Aβ

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