the use of transcytosis as a mechanism for transporting therapeutic drugs across the human blood–brain barrier (BBB). Exploiting the body's own transport mechanism can help to overcome the high selectivity of the BBB, which typically blocks the uptake of most therapeutic antibodies into the brain and central nervous system (CNS). The pharmaceutical company Genentech, after having synthesized a therapeutic antibody that effectively inhibited BACE1 enzymatic function, experienced problems transferring adequate, efficient levels of the antibody within the brain. BACE1 is the enzyme which processes amyloid precursor proteins into amyloid-β peptides, including the species that aggregate to form amyloid plaques associated with Alzheimer's disease. Molecules are transported across an epithelial or endothelial barrier by one of two routes: 1) a transcellular route through the intracellular compartment of the cell, or 2) a paracellular route through the extracellular space between adjacent cells. The transcellular route is also called transcytosis. Transcytosis can be receptor-mediated and consists of three steps: 1) receptor-mediated endocytosis of the molecule on one side of the cell, e.g. the luminal side; 2) movement of the molecule through the intracellular compartment typically within the endosomal system; and 3) exocytosis of the molecule to the extracellular space on the other side of the cell, e.g. the abluminal side. Transcytosis may be either unidirectional or bidirectional. Unidirectional transcytosis may occur selectively in the luminal to abluminal direction, or in the reverse direction, in the abluminal to luminal direction. Transcytosis is prominent in brain microvascular peptide and protein transport, because the brain microvascular endothelium, which forms the blood-brain barrier (BBB) in vivo, expresses unique, epithelial-like, high-resistance tight junctions. The brain endothelial tight junctions virtually eliminate the paracellular pathway of solute transport across the microvascular endothelial wall in brain. In contrast, the endothelial barrier in peripheral organs does not express tight junctions, and solute movement through the paracellular pathway is prominent at the endothelial barrier in organs other than the brain or spinal cord. Receptor-mediated transcytosis, or RMT, across the BBB is a potential pathway for drug delivery to the brain, particularly for biologic drugs such as recombinant proteins. The non-transportable drug, or therapeutic protein, is genetically fused to a transporter protein. The transporter protein may be an endogenous peptide, or peptidomimetic monoclonal antibody, which undergoes RMT across the BBB via transport on brain endothelial receptors such as the insulin receptor or transferrin receptor. The transporter protein acts as a molecular Trojan horse to