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Fig. 1 | Genes & Nutrition

Fig. 1

From: Peripheral metabolism of lipoprotein-amyloid beta as a risk factor for Alzheimer’s disease: potential interactive effects of APOE genotype with dietary fats

Fig. 1

Proposed plasma lipoprotein-amyloid effects on the neurovascular unit. Dietary fats are absorbed as nonesterified fatty acids on the apical membrane of duodenal enterocytes, re-sterified and transiently stored as cytoplasmic lipid droplets. Chylomicron assembly is continuous but can be stimulated by accumulation of enterocytic lipids. Nascent chylomicrons (CM) are secreted into lymphatics with apoproteins, including amyloid-beta (Aβ), which regulate CM metabolism. In circulation, triglyceride-rich CM are progressively hydrolyzed by endothelial lipoprotein lipase, abundant on the plasma membrane of capillary endothelia. Triglyceride-depleted CM remnants (RM) are cleared from blood via an ApoE-dependent high-affinity processes, principally via the LDL receptor which is expressed in abundance on liver hepatocytes. The residual delivery of CM lipids stimulates genesis of nascent very-low-density lipoproteins (VLDL), which like CM are rich in triglyceride and share the same metabolic pathway of lipase-mediated hydrolysis and remnant clearance. VLDL-Aβ secretion may also be exaggerated because of genetic or endocrine-based comorbidities. Exaggerated abundance of lipoprotein-Aβ (CM-Aβ & VLDL-Aβ) is associated with capillary dysfunction, including attenuation of tight junction proteins and extravazation to brain parenchyme of the lipoprotein-amyloid. ApoE anchors the Aβ containing lipoprotein remnants to extracellular matrices and thereafter for receptor and phagocytic uptake of remnant lipoproteins by glia and monocyte-derived macrophages. Lysosomal degradation within the macrophage results in lipoprotein breakdown and protein hydrolylsis concomitant with the release of inflammatory cytokines and prooxidants. Focal inflammation and oxidative stress compromises neuronal cell integrity. Amyloid liberation within the cell and/or following macrophage cell death heightens propensity for Aβ aggregation. Diets enriched in saturated fatty acids may drive lipoprotein-Aβ synthesis and secretion, compromise the capillary endothelia and increase endoplasmic reticulum and mitochondrial stress. ApoE E4 relative to ApoE E3 may slow hydrolysis of triglyceride lipolysis and have lower affinity for hepatic receptor-mediated clearance pathways. Increased ApoE E4-mediated capillary exposure to lipoprotein-Aβ exacerbates capillary stress. ApoE E4 may regulate binding to matrices or regulate phagocytic uptake by inflammatory cells

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