BackgroundThe growing body of evidence indicating the heterogeneity of Alzheimer’s disease (AD), coupled with disappointing clinical studies directed at a fit-for-all therapy, suggest that the development of a single magic cure suitable for all cases may not be possible. This calls for a shift in paradigm where targeted treatment is developed for specific AD subpopulations that share distinct genetic or pathological properties. Apolipoprotein E4 (apoE4), the most prevalent genetic risk factor of AD, is expressed in more than half of AD patients and is thus an important possible AD therapeutic target.ReviewThis review focuses initially on the pathological effects of apoE4 in AD, as well as on the corresponding cellular and animal models and the suggested cellular and molecular mechanisms which mediate them. The second part of the review focuses on recent apoE4-targeted (from the APOE gene to the apoE protein and its interactors) therapeutic approaches that have been developed in animal models and are ready to be translated to human. Further, the issue of whether the pathological effects of apoE4 are due to loss of protective function or due to gain of toxic function is discussed herein. It is possible that both mechanisms coexist, with certain constituents of the apoE4 molecule and/or its downstream signaling mediating a toxic effect, while others are associated with a loss of protective function.ConclusionApoE4 is a promising AD therapeutic target that remains understudied. Recent studies are now paving the way for effective apoE4-directed AD treatment approaches.

Background: Apolipoprotein E4 (apoE4) is the most prevalent genetic risk factor of Alzheimer’s disease (AD). Several studies suggest that the binding of apoE4 to its receptors (i.e., apoER2 and LRP-1) is associated with the internalization of the receptors and their accumulation in intracellular compartments. Importantly, this phenomenon also occurs with other, non-apoE, receptors. These observations lead to the hypothesis that the pathological effects of apoE4 are mediated by impairment in the life cycle and intracellular compartmentation of distinct receptors which belong to various systems. Thus, the present study examines the effects of APOE -genotype on the levels and compartmentation of membranal receptors including apoE receptors (apoER2 and LRP-1) and growth-factor receptors (InsulinR and VEGFR). Methods: Primary mouse neurons were prepared from either apoE3 or apoE4 targeted replacement (TR) mice or apoE-KO mice. The neurons were then evaluated for levels of the LRP-1, apoER2, VEGFR and InsulinR utilizing immunohistochemical staining. Additionally, external surface membranal levels of those receptors was evaluated via cell surface Biotinylation assay and ELISA. The extend of colocalization of the receptors with intracellular compartments was assessed by double labeling and confocal microscopy, followed by M1 colocalization analysis. Finally, CRISPR/Cas9 system was used to knock out LRP-1 and apoER2 and study their role in mediating the effects of apoE4 on the receptors. Results: Comparisons of the receptors’ levels in apoE4 and apoE3 primary neuronal cultures, revealed that apoE4 is associated with lower levels of the four receptors, specifically in the external membrane. Additionally, apoE4 affects the intracellular localization of these receptors in two main patterns: the first pattern was observed with LRP-1 and was associated with decreased receptor levels in numerous intracellular compartments. The second pattern, which was obtained with the other three receptors, was associated with their accumulation in early endosomes with a parallel decrease of their levels in the late endosomes. Conclusion: These results show that apoE4 drives the down regulation, and affects the intracellular trafficking of apoE and growth factor receptors. This provide a unifying mechanism via which apoE4 induces a wide range of pathological phenotypes seen in Alzheimer’s disease.