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 elucidated. A prevailing hypothesis incriminates the impaired ability of APOE4 to clear neurotoxic amyloid-β peptides (Aβ) from the brain as the main mechanism linking the apolipoprotein isoform to disease etiology. The 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 changes in the pathways of lipid homeostasis in the brains of mice expressing the human APOE4 vs. APOE3 isoform. Carriers of APOE4 had altered cholesterol turnover, an imbalance in the ratio of specific classes of phospholipids, lower levels of phosphatidylethanolamines bearing polyunsaturated fatty acids and an overall elevation in levels of monounsaturated fatty acids. These modifications in lipid homeostasis were related to increased production of Aβ peptides as well as augmented levels of tau and phosphorylated tau in primary neuronal cultures. This suite of APOE4-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.

APOE Peripheral and Brain Impact: APOE4 Carriers Accelerate Their Alzheimer Continuum and Have a High Risk of Suicide in PM2.5 Polluted Cities

“…APOE4 is a complex risk factor for AD and other neurodegenerative diseases, with multiple, heterogenous, and overlapping action mechanisms and molecular interactions [ 3 , 5 , 6 , 10 , 14 , 30 , 35 , 46 , 75 , 76 , 77 , 78 , 79 , 80 ]. Stuchell-Brereton et al [ 75 ] have shown that APOE4 is far more disordered and extended than previously described and retains conformational heterogeneity after binding lipids, which helps to understand the differences between the ε4 allele and protective variants of the protein.…”

“…Stuchell-Brereton et al [ 75 ] have shown that APOE4 is far more disordered and extended than previously described and retains conformational heterogeneity after binding lipids, which helps to understand the differences between the ε4 allele and protective variants of the protein. While there is not much controversy in stating APOE4 increases the risk of AD by driving earlier and more abundant amyloid pathology in the brains of APOE4 carriers [ 30 ], the work of Lazar et al [ 76 ] in mice expressing the human APOE4 vs. APOE3 isoform shows APOE4 carriers had altered cholesterol turnover, ratio imbalances of specific classes of phospholipids, low phosphatidylethanolamines bearing polyunsaturated fatty acids, and an elevation in monounsaturated fatty acids. More importantly, these changes in lipid homeostasis were related to increased production of Aβ peptides and higher levels of tau and phosphorylated tau in primary neuronal cultures [ 76 ].…”

“…While there is not much controversy in stating APOE4 increases the risk of AD by driving earlier and more abundant amyloid pathology in the brains of APOE4 carriers [ 30 ], the work of Lazar et al [ 76 ] in mice expressing the human APOE4 vs. APOE3 isoform shows APOE4 carriers had altered cholesterol turnover, ratio imbalances of specific classes of phospholipids, low phosphatidylethanolamines bearing polyunsaturated fatty acids, and an elevation in monounsaturated fatty acids. More importantly, these changes in lipid homeostasis were related to increased production of Aβ peptides and higher levels of tau and phosphorylated tau in primary neuronal cultures [ 76 ]. Tcw et al [ 77 ] investigated the effects of APOE4 on neural cells and isogenic human-induced pluripotent stem cells, as well as in human autopsies and in APOE-targeted replacement mice.…”

Interactions of amyloidogenic proteins with mitochondrial protein import machinery in aging-related neurodegenerative diseases

“…The ApoE cascade hypothesis does not include Aβ as a contributing factor in disease pathogenesis, stating that the biophysical and structural properties dependent of the ApoE isoform initiate a cascade of events driving AD and aging-related pathogenic condition (Martens et al, 2022). ApoE4 has been shown to alter lipid homeostasis and metabolism, leading to changes in lipid droplet formation, cholesterol turnover, and the PC/PE ratio (Farmer et al, 2019;Lazar et al, 2022;Yang et al, 2023). Consistent with MAM alterations, several lines of work support the involvement of ApoE in mitochondrial dysfunction as a contributing component to disease pathogenesis, including recent findings suggesting mitochondrial dysfunction influences ApoE expression and secretion (Dose et al, 2016;Martens et al, 2022;Wynne et al, 2023).…”