APOE and neuroenergetics: an emerging paradigm in Alzheimer's disease

Abstract

APOE is the major known genetic risk factor for late-onset Alzheimer's disease. Though relationships between APOE-encoded apolipoprotein E and β-amyloid are increasingly well described, mounting evidence supports wide-ranging effects of APOE on the brain. Specifically, APOE appears to affect brain network activity and closely related neuroenergetic functions that might be involved in vulnerability to neurodegenerative pathophysiology. These effects highlight the salience of further investigation into the diverse influences of APOE. Therefore, this article reviews the interplay between APOE and neuroenergetics and proposes areas for further investigation. This research might lead to the identification of novel therapeutic targets for the treatment and/or prevention of Alzheimer's disease.

Copyright © 2013 Elsevier Inc. All rights reserved.

Figures

Fig. 1

Medial view localizing abnormally low CMRgl (blue) in the PCC in young adult carriers of the APOE ε4 allele, and a summary of brain imaging results thus far reported in similarly-aged young adults and children (citations in text). Widespread changes in neuroenergetics and brain structure point to a neurodevelopmental role for APOE and early interference by the APOE ε4 allele, but this is yet to be confirmed. CMRgl=cerebral metabolic rate for glucose; PCC=posterior cingulate cortex; OXPHOS=oxidative phosphorylation; CO=cytochrome oxidase, Complex IV of the ETC; DMN=default mode network; DTI=diffusion tensor imaging

Fig. 2

Structural difference between apoE3 and apoE4. Domain interaction prevalent in apoE4 is predicated on the substitution of Arg for Cys at position 112 (Zhong & Weisgraber, 2009; reprinted with permission. © 2009 The American Society for Biochemistry and Molecular Biology. All rights reserved.)

Fig. 3

Summary of the effects of cell-type specific expression and aberrant processing of apoE4 in the brain. Astrocyte-expressed apoE is internalized by neurons, but apoE4 expression in astrocytes has been associated with ER stress that may impair astrocytes’ ability to contribute to brain energy flux. A smaller proportion of brain apoE expression is attributed to neurons: apoE4 expressed in neurons (but not that internalized from astrocytes) is highly susceptible to cleavage by AECE (apoE cleaving enzyme) in the secretory pathway becoming apoE(Δ272–299). ApoE4 cleaved by AECE is capable of escaping the secretory pathway, self-aggregating in the cytosol, increasing the fibrillization of tau, and interfering with mitochondrial transport and function.