Physiological amyloid-beta clearance in the periphery and its therapeutic potential for Alzheimer's disease.

ABSTRACT: Amyloid-beta (A?) plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). The physiological capacity of peripheral tissues and organs in clearing brain-derived A? and its therapeutic potential for AD remains largely unknown. Here, we measured blood A? levels in different locations of the circulation in humans and mice, and used a parabiosis model to investigate the effect of peripheral A? catabolism on AD pathogenesis. We found that blood A? levels in the inferior/posterior vena cava were lower than that in the superior vena cava in both humans and mice. In addition, injected (125)I labeled A?40 was located mostly in the liver, kidney, gastrointestinal tract, and skin but very little in the brain; suggesting that A? derived from the brain can be cleared in the periphery. Parabiosis before and after A? deposition in the brain significantly reduced brain A? burden without alterations in the expression of amyloid precursor protein, A? generating and degrading enzymes, A? transport receptors, and AD-type pathologies including hyperphosphorylated tau, neuroinflammation, as well as neuronal degeneration and loss in the brains of parabiotic AD mice. Our study revealed that the peripheral system is potent in clearing brain A? and preventing AD pathogenesis. The present work suggests that peripheral A? clearance is a valid therapeutic approach for AD, and implies that deficits in the A? clearance in the periphery might also contribute to AD pathogenesis.

SUBMITTER: Xiang Y 

PROVIDER: S-EPMC4575389 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature