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

Amyloid-beta (A beta) 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 beta and its therapeutic potential for AD remains largely unknown. Here, we measured blood A beta levels in different locations of the circulation in humans and mice, and used a parabiosis model to investigate the effect of peripheral A beta catabolism on AD pathogenesis. We found that blood A beta levels in the inferior/posterior vena cava were lower than that in the superior vena cava in both humans and mice. In addition, injected I-125 labeled A beta 40 was located mostly in the liver, kidney, gastrointestinal tract, and skin but very little in the brain; suggesting that A beta derived from the brain can be cleared in the periphery. Parabiosis before and after A beta deposition in the brain significantly reduced brain A beta burden without alterations in the expression of amyloid precursor protein, A beta generating and degrading enzymes, A beta 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 beta and preventing AD pathogenesis. The present work suggests that peripheral A beta clearance is a valid therapeutic approach for AD, and implies that deficits in the A beta clearance in the periphery might also contribute to AD pathogenesis.