Romanian Biotechnological Letters Copyright © 2016 University of Bucharest Vol. 21, No. 3, 2016 Printed in Romania. All rights reserved REVIEW Romanian Biotechnological Letters, Vol. 21, No. 3, 2016 11443 New Insights on Apoliprotein E Involvement in Brain Lipid Homeostasis Received for publication, September 7, 2015 Accepted, October 15, 2015 MĂDĂLINA DUMITRESCU 1 , ANCA VIOLETA GAFENCU 1* , ELENA VALERIA FUIOR 1 1 Institute of Cellular Biology and Pathology “N. Simionescu”, 8, B.P. Hasdeu Street, 050568, Bucharest, Romania * Corresponding author: Anca V Gafencu, Institute of Cellular Biology and Pathology “Nicolae Simionescu” of the Romanian Academy, 8, B.P. Hasdeu, 050568, Bucharest, Romania, Tel: +4021 3192327/222, e-mail: anca.gafencu@icbp.ro Abstract Apolipoprotein E (APOE) is a lipid transport protein which remarkably illustrates the structure- function paradigm through the isoform-specific effects it exerts in cardiovascular, neurological and immune pathologies. In the brain, APOE is mostly involved in cholesterol redistribution from the astrocytes to the neurons. However, APOE affects also other types of brain lipids, although in a more subtle and incompletely understood manner. Recent data revealed a major contribution of APOE in phosphatidyl inositol metabolism in an isoform-specific manner. This novel finding raises the possibility to identify unexplored molecular mechanisms in Alzheimer's disease. It may also provide a missing link between the presence of APOE ε4 allele and the increased risk of late-onset Alzheimer's disease at earlier age and serve as a foundation for new therapeutic approaches. In the end, we review a few therapeutic applications using APOE mimetic peptides in restoring the deranged brain glycosphingolipid metabolism as it occurs in lysosomal storage diseases. Keywords: Alzheimer Disease, astrocyte, cholesterol, amyloid beta 1. Introduction Apolipoprotein E (APOE) is a pivotal lipid transport protein associated with all lipoprotein classes, with the liver and the brain being the main biosynthesis sites in the body, as reviewed in (1). While hepatic APOE is involved in plasma lipid homeostasis by clearance of triglyceride and cholesterol rich-particles, brain APOE is essential for delivering cholesterol from astrocytes to neurons, processes reviewed in (2). Although lipoprotein metabolism may occur with significant differences in plasma as compared to the central nervous system (3), APOE dysregulation is prominent in both areas in two well-known pathologies. It was demonstrated that APOE deficiency induces atherosclerosis in humans (4) and mice (5, 6). Moreover, while the human APOE2 is correlated with cardiovascular diseases, APOE4 isoform is a risk factor for late-onset Alzheimer disease (AD) (7). APOE is essential to brain physiological status not only as a lipid shuttle, but also for the regulation of energetic demands (8), microcirculation (9), immunity, cell signalling (10). The brain is an organ particularly sensitive to metabolic variations. Although it represents only ~2% of the total body weight, it consumes about 20% of the total oxygen at a steady rate and it utilizes mainly glucose as its fuel. It is the most cholesterol-rich organ in the body. In the adult life, after neuronal cholesterol biosynthesis ceases, this essential component