Apolipoprotein E: Essential Catalyst of the Alzheimer Amyloid Cascade

Figure 2

Conceptual energy diagram of ApoE-catalyzed Aβ oligo/polymerization. Although Aβ can polymerize spontaneously, the reaction is greatly promoted by apoE in vitro and in vivo. This catalysis can be understood in terms of the energy diagram shown. The first energy change, a reduction, occurs as apoE binds to amino acids 12–28 of Aβ, with different apoE isoforms binding with different affinities. Then apoE apparently alters the structure of its bound Aβ to a higher-energy β-sheet conformation (the transition state), which allows additional Aβ molecules to add and form a larger oligomer or fibril. These products have lower energy than either the transition state or the initial reactants (apoE and Aβ), thus driving the reaction to completion. Because the energy of the apoE-Aβ transition state is lower than either the transition state of monomeric Aβ in a β-sheet conformation, the oligo/polymerization reaction is effectively catalyzed by apoE. ApoE4 evidently forms the lowest energy transition state and thus strongly catalyzes the reaction, apoE3 catalyzes the reaction less well, and apoE2 likely forms such a high energy transition state that it effectively inhibits the spontaneous Aβ polymerization reaction. Antichymotrypsin (ACT), which binds to Aβ amino acids 1–12, also catalyzes Aβ polymerization, while Aβ antibodies can either promote Aβ fibrillization themselves or interfere with ACT or apoE-catalyzed polymerization. Molecules, including antibodies, that prevent apoE or ACT binding to Aβ are being developed as AD therapies that leave the normal physiological functions of Aβ and apoE or ACT intact, while blocking their pathological interaction.