Lipid Dys-Homeostasis Contributes to APOE4 Associated AD Pathology

Abstract

The association of the APOE4 (vs APOE3) isoform with an increased risk of Alzheimer’s Disease (AD) is unequivocal, but the underlying mechanisms remain incompletely elu-cidated. A prevailing hypothesis incriminates the impaired ability of APOE4 to clear neurotoxic amyloid-β peptides (Aβ) from the brain as the main mechanism linking apolipoprotein isoform to disease aetiology. APOE protein mediates lipid transport both within the brain and from the brain to the periphery, suggesting that lipids may be potential co-factors in APOE4-associated physiopathology. The present study reveals several alterations in pathways of lipid homeostasis in the brains of mice expressing the human APOE4 versus APOE3 isoform. Carriers of APOE4 had deficient cholesterol turnover, an imbalance in the ratio of specific classes of phospholipids, lower levels of phosphatidylethanolamines bearing poly-unsaturated fatty acids and an overall eleva-tion in levels of monounsaturated fatty acids. These modifications in lipid homeostasis were related with increased production of Aβ peptides as well as augmented levels of tau and phosphorylated tau in primary neuronal cultures. This suite of AP-OE4-associated anomalies in lipid homeostasis and neurotoxic protein levels may be related to the accrued risk for AD in APOE4 carriers and provides novel insights into potential strategies for therapeutic intervention.

Assessment of Serum level of Apolipoprotein E4 in Patients with Vitiligo: A Comparative Review

“…Variations in lipid metabolism have been linked to a number of illnesses, including vitiligo. ApoE4, which is involved in lipid transport and metabolism, may lead to abnormalities in lipid homeostasis that influence the function of melanocytes [26]. It has been postulated that ApoE4-mediated deregulation of lipid metabolism might disturb the balance of lipid components required for proper melanocyte activity.…”