Sink Hypothesis and Therapeutic Strategies for Attenuating Aβ Levels

Amyloid beta (A beta) plaque, comprised mainly by A beta peptides, is an important pathology of Alzheimer's brains. Major efforts have been devoted to targeting this neurotoxic A beta peptide for discovering disease-modifying treatments for Alzheimer's disease. Inasmuch as A beta is found in both the brain and the periphery, it is hypothesized that there is some form of equilibrium for the A beta in the brain and the periphery such that A beta can be transported across the blood-brain barrier. By modulating the periphery A beta levels, it is predicted that the brain A beta levels will undergo concomitant changes, forming the basis of the sink hypothesis for A beta lowering strategies. In this review, the significance and implication of this sink hypothesis as well as how the sink hypothesis may contribute to the recent A beta-based drug discovery in AD are discussed. Ultimately, the validity of the sink hypothesis will be resolved when the appropriate A beta agents are being tested in the clinic.