Molecular Insight into the Therapeutic Promise of Targeting APOE4 for Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease that causes chronic cognitive dysfunction. Most of the AD cases are late onset, and the apolipoprotein E (APOE) isoform is a key genetic risk factor. The APOE gene has 3 key alleles in humans including APOE2, APOE3, and APOE4. Among them, APOE4 is the most potent genetic risk factor for late-onset AD (LOAD), while APOE2 has a defensive effect. Research data suggest that APOE4 leads to the pathogenesis of AD through various processes such as accelerated beta-amyloid aggregations that raised neurofibrillary tangle formation, cerebrovascular diseases, aggravated neuroinflammation, and synaptic loss. However, the precise mode of actions regarding in what way APOE4 leads to AD pathology remains unclear. Since APOE contributes to several pathological pathways of AD, targeting APOE4 might serve as a promising strategy for the development of novel drugs to combat AD. In this review, we focus on the recent studies about APOE4-targeted therapeutic strategies that have been advanced in animal models and are being prepared for use in humans for the management of AD.

Figure 1

Schematic presentation of the human APOE genotype and APOE polymorphisms. The human APOE gene is situated in the long arm of chromosome 19. In exon 4 of chromosome 19, two nonsynonymous single nucleotide polymorphisms (SNPs) including rs429358 and rs7412 produce 3 main allelic variants (E2, E3, and E4). The resulting APOE2, APOE3, and APOE4 isoforms vary from one another at amino acid residues 112 or 158.

Figure 2

Classification of APOE-targeted treatment strategies for Alzheimer's disease.

Figure 3

Increasing lipidation of the astrocytic pool of APOE. APOE is principally produced by astrocytes in the brain. Activation of nuclear hormone receptors including LXR and RXR plays an essential role in the expression of APOE and ABCA1. Moreover, ABCA1 is very important for the lipidation of APOE and increasing the expression of ABCA1 contributes to enhanced lipidation of all APOE polymorphisms (indicated by red arrows). It is assumed that enhanced lipidation of APOE will be valuable for several AD-relevant endpoints.

Figure 4

Editing of APOE4 by CRISPR to generate an APOE3-like structure. The APOE4 allele is generally produced by APOE chromosome 19 (19q13.2). The coding of DNA for APOE4 varies from APOE3, which is considered as the benign gene for AD, by only 1 nucleotide (explicitly, the 112th position is cysteine in APOE3 and arginine in the case of APOE4). Particularly, the CRISPR method could be used for converting the APOE4 gene into APOE3.

Figure 5

APOE4 structure correctors can disrupt ApoE4 domain-domain interaction. In the N-terminal domain, Arg-61 interacts with Glu-255 in the C-terminal domain in APOE4. APOE4 structure correctors (PH002 and GIND25) that are expected to interact with APOE4 in the region of Arg-61 would interrupt domain-domain interaction and transform APOE4 to an APOE3-like molecule.