Apolipoprotein E Sets the Stage: Response to Injury Triggers Neuropathology

Abstract

Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease and is associated with poor clinical outcome following traumatic brain injury and other neuropathological disorders. Protein instability and an isoform-specific apoE property called domain interaction are responsible for these neuropathological effects. ApoE4 is the most neurotoxic isoform and can induce neuropathology through various cellular pathways. Neuronal damage or stress induces apoE synthesis as part of the repair response; however, when apoE4 is expressed in neurons, its unique conformation makes it susceptible to proteolysis, resulting in the generation of neurotoxic fragments. These fragments cause pathological mitochondrial dysfunction and cytoskeletal alterations. Here, we review data supporting the hypothesis that apoE4 (> apoE3 > apoE2) has direct neurotoxic effects and highlight studies showing that blocking domain interaction reverses these detrimental effects.

Binding of Apolipoprotein E Inhibits the Oligomer Growth of Amyloid-β Peptide in Solution as Determined by Fluorescence Cross-correlation Spectroscopy

“…In addition, elevated local concentrations of apoE draw physiological connections to our findings. In response to injury, neurons rapidly release large amounts of apoE (41), where its accumulation in the extracellular matrix (42) results in effective concentrations exceeding the levels applied here. Future FCCS work will also consider the interaction of lipid-bound apoE isoforms and A␤ using FCCS as previous measurements have shown a higher affinity for oligomeric A␤ when the protein is assembled in HDL-like lipoprotein particles (29).…”

Lipoproteins and Diseases of the Brain

“…These minor variations cause a change in the structure and function of apoE, which eventually leads to distinct disease mechanisms in AD [21]. ApoE4 has an arginine at residue 112 that connects the N terminus (Arg 61) to the C terminus (Glu 255) to form a folded structure of apoE called domain interaction [22].…”

“…When lipidated, apoE4 is known to be toxic to neurons through various pathogenic pathways such as Aβ aggregation and apoE fragment formation [21]. The effect of apoE4 on neurons when it is not lipidated, however, remains unclear.…”

Role of Apo E and superoxide dismutase in patients with obstructive lung diseases

“…[10][11][12] It has three major isoforms (Apo E2, Apo E3, and Apo E4) with different effects on lipid and neuronal homeostasis. 13 Intracellular Apo E may regulate various cellular processes physiologically or pathophysiologically.…”