Therapeutic approaches targeting Apolipoprotein E function in Alzheimer's disease

Abstract

One of the primary genetic risk factors for Alzheimer's disease (AD) is the presence of the Ɛ4 allele of apolipoprotein E (APOE). APOE is a polymorphic lipoprotein that is a major cholesterol carrier in the brain. It is also involved in various cellular functions such as neuronal signaling, neuroinflammation and glucose metabolism. Humans predominantly possess three different allelic variants of APOE, termed E2, E3, and E4, with the E3 allele being the most common. The presence of the E4 allele is associated with increased risk of AD whereas E2 reduces the risk. To understand the molecular mechanisms that underlie APOE-related genetic risk, considerable effort has been devoted towards developing cellular and animal models. Data from these models indicate that APOE4 exacerbates amyloid β plaque burden in a dose-dependent manner. and may also enhance tau pathogenesis in an isoform-dependent manner. Other studies have suggested APOE4 increases the risk of AD by mechanisms that are distinct from modulation of Aβ or tau pathology. Further, whether plasma APOE, by influencing systemic metabolic pathways, can also possibly alter CNS function indirectly is not complete;y understood. Collectively, the available studies suggest that APOE may impact multiple signaling pathways and thus investigators have sought therapeutics that would disrupt pathological functions of APOE while preserving or enhancing beneficial functions. This review will highlight some of the therapeutic strategies that are currently being pursued to target APOE4 towards preventing or treating AD and we will discuss additional strategies that holds promise for the future.

Keywords: Alzheimer’s disease; Amyloid β; Apolipoprotein E; Tau; Therapy.

Fig. 1

Congruence of the effects of apoE between human studies, mouse models of AD and in vitro cell culture models. apoE influences multiple pathways in the AD cascade in an isoform-dependent manner. We compared the concurrence of available research data in mouse models and in vitro models versus clinical studies with human patients. Pathways indicated in the green color indicate a broad consensus of APOE isoform effect between mice, men and in vitro models where E4 is associated with an increased pathological risk when compared to E3 or E2 isoforms (E4>E3>E2). Data from the pathways indicated in yellow background are not in complete congruence between human studies, mouse model experiments and in vitro data. Interestingly, even within a set of studies in a given experimental system, there is disagreement in between the observations, which is marked by superscripted symbols that refers to the disparate studies. The symbols (< or >) indicate the order of increased pathological effect for the APOE isoforms. The effects listed here are specific to only classical AD pathology and excludes data on α-synuclein and TDP43 which are associated with diseases such as PDD and DLB. *, conflicting reports [see ref 40]; #, conflicting reports [see ref 41]; ¶, studies compared APOE4 TR, Apoe KO, and wild type C57BL6J mice. The references presented are representative and not an exhaustive list

Fig. 2

A schematic to illustrate the various targets for APOE-based AD therapeutics. See the main text for details. Black arrows pointing to the red text boxes indicate a mode of intervention while blue arrows indicate the movement of the drug or protein. Black solid arrows crossing the BBB show permeability while black dashed arrows show BBB semi-permeability. ABCA1: ATP-binding cassette transporter A1; LDLR: low density lipoprotein receptor; APOE: apolipoprotein E; Aβ: amyloid-β; TREM2: triggering receptor expressed on myeloid cells 2