Lipids and lipoproteins may play a role in the neuropathology of Alzheimer's disease

Abstract

Alzheimer's disease (AD) and other classes of dementia are important public health problems with overwhelming social, physical, and financial effects for patients, society, and their families and caregivers. The pathophysiology of AD is poorly understood despite the extensive number of clinical and experimental studies. The brain's lipid-rich composition is linked to disturbances in lipid homeostasis, often associated with glucose and lipid abnormalities in various neurodegenerative diseases, including AD. Moreover, elevated low-density lipoprotein (LDL) cholesterol levels may be related to a higher probability of AD. Here, we hypothesize that lipids, and electronegative LDL (L5) in particular, may be involved in the pathophysiology of AD. Although changes in cholesterol, triglyceride, LDL, and glucose levels are seen in AD, the cause remains unknown. We believe that L5-the most electronegative subfraction of LDL-may be a crucial factor in understanding the involvement of lipids in AD pathology. LDL and L5 are internalized by cells through different receptors and mechanisms that trigger separate intracellular pathways. One of the receptors involved in L5 internalization, LOX-1, triggers apoptotic pathways. Aging is associated with dysregulation of lipid homeostasis, and it is believed that alterations in lipid metabolism contribute to the pathogenesis of AD. Proposed mechanisms of lipid dysregulation in AD include mitochondrial dysfunction, blood-brain barrier disease, neuronal signaling, inflammation, and oxidative stress, all of which lead ultimately to memory loss through deficiency of synaptic integration. Several lipid species and their receptors have essential functions in AD pathogenesis and may be potential biomarkers.

Keywords: Alzheimer’s disease; LDLR; LOX-1; cholesterol; electronegative LDL; lipids.

Figure 1

Composition and structural characteristics of regular (L1) and electronegative (L5) LDL in humans. The apolipoprotein content specifies the structure, receptor interactions, assembly, and metabolism of these lipoproteins. The L5 subtype differs from regular LDL because of its additional apolipoproteins. Apo(a), apolipoprotein small (a); ApoA1, apolipoprotein-A1; ApoB100, Apolipoprotein-B100; ApoCIII, apolipoprotein-CIII; APOE, apolipoprotein-E.

Figure 2

Illustration showing L5 and LDL signaling pathways through vascular endothelial cell membrane receptors. Endothelial cells have receptors for oxidized lipoproteins and machinery for lipoprotein receptor-mediated endocytosis. L5 signals are taken up through LOX-1 and PAFR receptors, whereas regular LDL and its subtypes (L1–L4) are internalized by LDLR. LDLR, a transmembrane glycoprotein found on most cell surfaces, governs LDL uptake and its subsequent lysosomal degradation. LDL is transported through endothelial cells using a process called receptor-mediated transcytosis. This transportation involves receptors like SRB1, ALK1, or LDLR as well as a direct transcytosis mechanism. In contrast, signaling through PAFR and LOX-1 triggers PI3K-PKC activation leading to AKT phosphorylation and reduced cAMP levels, while facilitating granule release. LOX-1 receptors are notably abundant in the human aorta, especially in atherosclerosis-prone areas. Exposure of endothelial cells to L5 causes a three-fold increase in membrane-bound LOX-1 levels. Arrows in the figure indicate the direction or influence of signaling pathways. Green arrows represent stimulation or activation, and red arrows with an end bar signify inhibition or suppression. ALK1, activin receptor-like kinase 1; Akt, protein kinase-B; Bcl2, B-cell lymphoma 2 (antiapoptotic protein); Bcl-xl, B-cell lymphoma extra-large (antiapoptotic protein); CRP, C-reactive protein; EC, endothelial cell; eNOS, endothelial NOS; FGF2, fibroblast-growth factor-2 (basic); FGF2R, fibroblast-growth factor receptor-2; FOXO, forkhead box transcription factor subgroup O; L5, electronegative LDL; LDLR, LDL-receptor; LOX-1, lectin like oxidized LDL receptor 1; PAFR, platelet activating factor-receptor; PI3K, phosphoinositide-3-kinase; RAP, LDL receptor–associated protein; SR-B1, scavenger receptor B1; TNF-α, tumor necrosis factor-alpha; TNFR, TNFα receptor; TS20-TS92, LOX-1 neutralizing-antibodies.

Figure 3

Schematic representation of L5 signaling pathways through various membrane receptors in platelets. Akt, protein kinase-B; cAMP, cyclic AMP; L5, electronegative LDL; LDLR, LDL receptor; LOX-1, lectin-like oxidized LDL receptor 1; PAFR, platelet activating factor receptor; pAKT, phosphorylated protein kinase-B; P2Y12, purinergic receptor P2Y G protein-coupled 12; PI3K, phosphoinositide-3-kinase; RAP, LDL receptor–associated protein; TS20/TS92, LOX-1 neutralizing-antibodies.