Connection between the Altered HDL Antioxidant and Anti-Inflammatory Properties and the Risk to Develop Alzheimer’s Disease: A Narrative Review

Figure 2

Role of HDL accessory proteins in AD physiopathology. Myeloperoxidase (MPO) participates in BBB breakdown by inducing the production of ROS (1) or by increasing neutrophil recruitment through interaction with the brain endothelium (2). MPO and serum amyloid A (SAA) may interact with Aβ plaques, inducing cytokine release and thus exacerbating neuroinflammation (3). In the CNS, SAA can activate glial cells, inducing the secretion of inflammatory cytokines through the activation of the inflammasome (4) and the modulation of the Toll-like receptors (TLR) (5). Moreover, SAA could directly contribute to the BBB breakdown by decreasing the expression of claudin-5, one of the tight junction components (6). SAA may induce the dissociation of apolipoprotein E (ApoE) from HDL-like particles present in the cerebrospinal fluid (CSF) (7), producing particles less able to bind Aβ and thus to mediate its clearance through the lipoprotein receptors (8). SAA enrichment could also affect CSF HDL function by interfering with their functions in mediating the brain cholesterol transport, essential to provide cholesterol to neurons (9). Lipoprotein phospholipase A2 (Lp-PLA2) produces phosphatidylcholine by enzymatic hydrolysis, a mediator of inflammatory stress in brain endothelial cells, increasing endothelial permeability, thus potentially affecting BBB integrity (10). Moreover, Lp-PLA2 activity can promote the expression of TNF-α, a key cytokine responsible for increased neuroinflammation (11). The decrease of selenium bioavailability could affect the glutathione peroxidase-3 (GPx-3) activity, negatively influencing the antioxidant defense mechanisms implicated in the removal of H₂O₂ and neutralization of lipid peroxides (12). The role of paraoxonase-3 (PON3) in AD is still under investigation, and the hypothesis is that it is produced by the liver and reaches the CNS by crossing the BBB in discoidal HDLs via an unknown mechanism [38] (13), as also hypothesized for PON1 [27, 28].