Soluble apoE/Aβ complex: mechanism and therapeutic target for APOE4-induced AD risk

Abstract

The APOE4 allele of apolipoprotein E (apoE) is the greatest genetic risk factor for Alzheimer’s disease (AD) compared to APOE2 and APOE3. Amyloid-β (Aβ), particularly in a soluble oligomeric form (oAβ), is considered a proximal cause of neurodegeneration in AD. Emerging data indicate that levels of soluble oAβ are increased with APOE4, providing a potential mechanism of APOE4-induced AD risk. However, the pathway(s) by which apoE4 may increase oAβ levels are unclear and the subject of continued inquiry. In this editorial review, we present the hypothesis that apoE isoform-specific interactions with Aβ, namely apoE/Aβ complex, modulate Aβ levels. Specifically, we propose that compared to apoE3, apoE4-containing lipoproteins are less lipidated, leading to less stable apoE4/Aβ complexes, resulting in reduced apoE4/Aβ levels and increased accumulation, particularly of oAβ. Evidence that support or counter this argument, as well as the therapeutic significance of this pathway to neurodegeneration, are discussed.

Amyloid-β Pathology and APOE Genotype Modulate Retinoid X Receptor Agonist Activity in Vivo

“…However, using a three-step sequential protein extraction protocol, TBS, TBSX (TBS containing Triton X-100) and formic acid (FA), the reduced levels of apoE4 are seen only in the TBSX fraction, indicating that apoE4 is less lipoprotein-associated and/or less lipidated (31). Additional data from our group and others support the pathway that the reduced lipoprotein association/lipidation of apoE4 (31,35) results in lower levels of apoE4/A␤ complex and higher levels of oA␤ (31,33), compromising synaptic viability. Thus, EFAD mice allow the preclinical analysis of RXR agonists in the presence of h-APOE.…”

“…By ELISA, oA␤ levels are increased with APOE4 and AD in human CSF, and both soluble A␤42 and soluble oA␤ levels are higher in E4FAD mice compared with E3FAD mice (31,33). Furthermore, although data are varied, Bex has previously been demonstrated to lower soluble A␤ in some FAD-Tg models (13)(14)(15)(16) and in one case oA␤ (13).…”

“…RXR Agonists Increase ApoE/A␤ Complex Levels in E4FAD-HP-A potential consequence of RXR agonist-induced increased apoE4 lipoprotein association is increased apoE/A␤ complex levels (33,52). To determine the effect of APOE genotype on apoE/A␤ complex levels, we previously developed an apoE/A␤ complex ELISA and demonstrated that apoE/A␤ complex levels are lower with AD and APOE4 in human CSF and with APOE4 in the TBS extracts of EFAD mice (33,52).…”

“…To determine the effect of APOE genotype on apoE/A␤ complex levels, we previously developed an apoE/A␤ complex ELISA and demonstrated that apoE/A␤ complex levels are lower with AD and APOE4 in human CSF and with APOE4 in the TBS extracts of EFAD mice (33,52). In this study, both RXR agonists increased apoE/A␤ complex levels by gavage (T1) and hydrogel (T2) by ϳ70 and 100%, respectively, compared with VC when assessed by ELISA (Fig.…”

“…Despite representing more than half of all AD patients, APOE4 carriers are often omitted from clinical trials because they fail to respond or respond anomalously (27)(28)(29)(30). Although the impact of h-APOE on CNS function is multifactorial, compared with APOE3, APOE4 increases insoluble and soluble A␤ levels in FAD-Tg mice (31) and in AD patients (32)(33)(34). However, the effects of RXR agonists on A␤ levels in the presence of h-APOE are unclear.…”