APOE genotype and stress response - a mini review.

Janina Dose,Patricia Huebbe,Almut Nebel,Gerald Rimbach

doi:10.1186/s12944-016-0288-2

Abstract

The APOE gene is one of currently only two genes that have consistently been associated with longevity. Apolipoprotein E (APOE) is a plasma protein which plays an important role in lipid and lipoprotein metabolism. In humans, there are three major APOE isoforms, designated APOE2, APOE3, and APOE4. Of these three isoforms, APOE3 is most common while APOE4 was shown to be associated with age-related diseases, including cardiovascular and Alzheimer’s disease, and therefore an increased mortality risk with advanced age. Evidence accumulates, showing that oxidative stress and, correspondingly, mitochondrial function is affected in an APOE isoform-dependent manner. Accordingly, several stress response pathways implicated in the aging process, including the endoplasmic reticulum stress response and immune function, appear to be influenced by the APOE genotype. The investigation and development of treatment strategies targeting APOE4 have not resolved any therapeutic yet that could be entirely recommended. This mini-review provides an overview on the state of research concerning the impact of the APOE genotype on stress response-related processes, emphasizing the strong interconnection between mitochondrial function, endoplasmic reticulum stress and the immune response. Furthermore, this review addresses potential treatment strategies and associated pitfalls as well as lifestyle interventions that could benefit people with an at risk APOE4 genotype.

Highlights

apolipoprotein E (APOE) genotype and cellular stress response - linking APOE to the aging process Increasing evidence links the APOE genotype to the cellular stress response and to the aging process
APOE produced by macrophages plays a pivotal role in the so-called reverse cholesterol transport, where excess cholesterol from peripheral tissues is redirected via APOE-containing high density lipoprotein (HDL) particles to the liver for elimination [22, 23]
While some reports show that APOE4 is positively associated with markers of oxidative stress, other studies report no significant differences between the two APOE isoforms (similar levels of F2-isoprostane and thiobarbituric acid-reactive substances in APOE3 and APOE4 targeted replacement (TR) mice; [60])

Summary

Background

General relevance of the topic Aging is characterized by both a proceeding decline in biological functions and a decreased stress resistance [1]. APOE produced by macrophages plays a pivotal role in the so-called reverse cholesterol transport, where excess cholesterol from peripheral tissues is redirected via APOE-containing high density lipoprotein (HDL) particles to the liver for elimination [22, 23] By these functions, APOE is fundamentally involved in the lipid and cholesterol homeostasis. Instead of a direct interaction of the C- and N-terminal domain in APOE4, Frieden and Garai [41] suggested that the positive charge of arginine at position 112 in the APOE4 protein is propagated to the C-terminal domain resulting in structural changes This view is substantiated by recent computational simulations which showed more contacts between the N- and C- terminal domain in APOE4, but with Arg and Glu255 appearing rather noninvolved [48]. Gerdes et al [53] suggest entitling APOE a “frailty gene” rather than referring to it as a determinant of longevity

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Findings

Conclusion and outlook