Apolipoprotein e: essential catalyst of the Alzheimer amyloid cascade

Abstract

The amyloid cascade hypothesis remains a robust model of AD neurodegeneration. However, amyloid deposits contain proteins besides Aβ, such as apolipoprotein E (apoE). Inheritance of the apoE4 allele is the strongest genetic risk factor for late-onset AD. However, there is no consensus on how different apoE isotypes contribute to AD pathogenesis. It has been hypothesized that apoE and apoE4 in particular is an amyloid catalyst or "pathological chaperone". Alternatively it has been posited that apoE regulates Aβ clearance, with apoE4 been worse at this function compared to apoE3. These views seem fundamentally opposed. The former would indicate that removing apoE will reduce AD pathology, while the latter suggests increasing brain ApoE levels may be beneficial. Here we consider the scientific basis of these different models of apoE function and suggest that these seemingly opposing views can be reconciled. The optimal therapeutic target may be to inhibit the interaction of apoE with Aβ rather than altering apoE levels. Such an approach will not have detrimental effects on the many beneficial roles apoE plays in neurobiology. Furthermore, other Aβ binding proteins, including ACT and apo J can inhibit or promote Aβ oligomerization/polymerization depending on conditions and might be manipulated to effect AD treatment.

Figure 1

ApoE promotes Aβ Fibril formation in brain and Aβ clearance from the blood. Data from both in vitro and in vivo experiments indicate that apoE, especially apoE4 promotes the polymerization of Aβ into oligomers and polymers that accumulate in the brain and are difficult to clear. In contrast, the concentration of apoE is higher in the blood, while those of Aβ species are equivalent to or lower than in the brain, promoting the formation and clearance of equimolar apoE-Aβ complexes.

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.