Fig. 20
Simplified outline of Aβ transport across the blood–brain barrier. Possible movements of Aβ are shown by solid or dashed lines with arrowheads indicating the principal direction. Endocytotic and exocytotic vesicles are shown as invaginations of the membranes. There is intracellular processing once the vesicles have been endocytosed. Aβ from ISF can bind directly to LRP1 on the abluminal membrane with the complex then being incorporated into a clathrin coated pit which can be endocytosed. The Aβ-LRP1 complex is stabilized by binding of the phosphatidylinositol-binding clathrin assembly protein (PICALM). Aβ in ISF can also be complexed with any of the forms of apoE, 2, 3 or 4 or with clusterin. Aβ-apoE2 and Aβ-apoE3 are substrates for interaction with LRP1 and endocytosis. By contrast Aβ-apoE4 inhibits LRP1 mediated endocytosis (dotted line), but can be endocytosed slowly after binding with the very low density lipoprotein receptor (VLDLR). Aβ-clusterin is a substrate for LRP2 mediated endocytois with transport across the blood–brain barrier to plasma. As Aβ-clusterin can also be transported in the opposite direction by LRP2-mediated endocytosis this is almost certainly by transcytosis of vesicles with LRP2 in the membrane. Vesicles with LRP1 in the membrane are also thought to discharge their contents on the far side of the barrier—i.e. this is transcytosis [465]. Some of the intracellular processing steps for the LRP1 vesicles are now known [452, 658]. Aβ is also transported from plasma to ISF. Aβ clusterin can be transported by LRP2 vesicles, but on the plasma side almost all of the LRP2 receptors are occupied by clusterin (dotted double headed arrow) rather than Aβ-clusterin which greatly reduces blood-to-brain transport by this route. Aβ is however, endocytosed after binding to the receptor for advanced glycation products, RAGE, and somehow transported to the brain side. Pgp may, in a manner which has not been well defined, assist transfer of Aβ from the endothelial cells to plasma whether it has entered the cells from ISF, via the LRP1 system, or from plasma, via the RAGE system. Figure based on [452, 464, 465]