Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders

Abstract

Apolipoprotein (apo) E was initially described as a lipid transport protein and major ligand for low density lipoprotein (LDL) receptors with a role in cholesterol metabolism and cardiovascular disease. It has since emerged as a major risk factor (causative gene) for Alzheimer's disease and other neurodegenerative disorders. Detailed understanding of the structural features of the three isoforms (apoE2, apoE3, and apoE4), which differ by only a single amino acid interchange, has elucidated their unique functions. ApoE2 and apoE4 increase the risk for heart disease: apoE2 increases atherogenic lipoprotein levels (it binds poorly to LDL receptors), and apoE4 increases LDL levels (it binds preferentially to triglyceride-rich, very low density lipoproteins, leading to downregulation of LDL receptors). ApoE4 also increases the risk for neurodegenerative diseases, decreases their age of onset, or alters their progression. ApoE4 likely causes neurodegeneration secondary to its abnormal structure, caused by an interaction between its carboxyl- and amino-terminal domains, called domain interaction. When neurons are stressed or injured, they synthesize apoE to redistribute cholesterol for neuronal repair or remodeling. However, because of its altered structure, neuronal apoE4 undergoes neuron-specific proteolysis, generating neurotoxic fragments (12-29 kDa) that escape the secretory pathway and cause mitochondrial dysfunction and cytoskeletal alterations, including tau phosphorylation. ApoE4-associated pathology can be prevented by small-molecule structure correctors that block domain interaction by converting apoE4 to a molecule that resembles apoE3 both structurally and functionally. Structure correctors are a potential therapeutic approach to reduce apoE4 pathology in both cardiovascular and neurological disorders.

Keywords: Alzheimer’s disease; ApoE; Atherosclerosis; Cholesterol; Small-molecule structure correctors.

Fig. 1

Structures of apoE3 and apoE4. a ApoE4 displays domain interaction caused by an ionic interaction between Arg-61 and Glu-255. This structural feature of apoE4 (apoE4 > apoE3 > apoE2) alters its function in cardiovascular and neurological disorders. b Small-molecule apoE4 structure correctors block domain interaction and convert apoE4 to an apoE3-like molecule structurally and functionally. c Injury of neurons induces apoE expression. When neurons are stressed or injured, they synthesize apoE to function in lipid redistribution for neuronal repair and remodeling. In this model, apoE4 is recognized as structurally abnormal and undergoes proteolytic cleavage, generating several neurotoxic fragments (12–29 kDa) that escape the secretory pathway, enter the cytosol, and cause mitochondrial dysfunction and tau phosphorylation (Tau-PO₄), ultimately causing cell death. ApoE4SC, apoE4 structure corrector. Modified from ref. . Copyright 2012 American Chemical Society