Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer's diseases

Abstract

Apolipoprotein (apo) E is a multifunctional protein with central roles in lipid metabolism, neurobiology, and neurodegenerative diseases. It has three major isoforms (apoE2, apoE3, and apoE4) with different effects on lipid and neuronal homeostasis. A major function of apoE is to mediate the binding of lipoproteins or lipid complexes in the plasma or interstitial fluids to specific cell-surface receptors. These receptors internalize apoE-containing lipoprotein particles; thus, apoE participates in the distribution/redistribution of lipids among various tissues and cells of the body. In addition, intracellular apoE may modulate various cellular processes physiologically or pathophysiologically, including cytoskeletal assembly and stability, mitochondrial integrity and function, and dendritic morphology and function. Elucidation of the functional domains within this protein and of the three-dimensional structure of the major isoforms of apoE has contributed significantly to our understanding of its physiological and pathophysiological roles at a molecular level. It is likely that apoE, with its multiple cellular origins and multiple structural and biophysical properties, is involved widely in processes of lipid metabolism and neurobiology, possibly encompassing a variety of disorders of neuronal repair, remodeling, and degeneration by interacting with different factors through various pathways.

Keywords: Alzheimer's disease; ApoE; Lipid metabolism; Mouse model.

Figure 1. ApoE isoforms and their properties

E2, apoE2; E3, apoE3; E4, apoE4.

Figure 2. ApoE4 domain interaction

In apoE4 (left), arginine 112 orients the side chain of arginine 61 into the aqueous environment, where it can interact with glutamic acid 255, resulting in interaction between the N-terminal and C-terminal domains. In apoE3 (right), arginine 61 is not available to interact with residues in the C-terminal domain, resulting in a very different overall conformation.

Figure 3. ApoE proteolysis and AD

In response to stressors and injurious agents, neurons turn on or increase their expression of apoE to repair or remodel the damaged neurons. However, neuronal apoE undergoes proteolytic processing, which generates C-terminal truncated fragments of apoE; apoE4 is more susceptible than apoE3 to the cleavage. These apoE fragments cause cytoskeletal changes, such as tau phosphorylation, neurofibrillary tangle formation, and mitochondrial dysfunction, finally leading to neurodegeneration.