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

Abstract

The protein composition of high-density lipoprotein (HDL) is extremely fluid. The quantity and quality of protein constituents drive the multiple biological functions of these lipoproteins, which include the ability to contrast atherogenesis, sustained inflammation, and toxic effects of reactive species. Several diseases where inflammation and oxidative stress participate in the pathogenetic process are characterized by perturbation in the HDL proteome. This change inevitably affects the functionality of the lipoprotein. An enlightening example in this frame comes from the literature on Alzheimer's disease (AD). Growing lines of epidemiological evidence suggest that loss of HDL-associated proteins, such as lipoprotein phospholipase A2 (Lp-PLA2), glutathione peroxidase-3 (GPx-3), and paraoxonase-1 and paraoxonase-3 (PON1, PON3), may be a feature of AD, even at the early stage. Moreover, the decrease in these enzymes with antioxidant/defensive action appears to be accompanied by a parallel increase of prooxidant and proinflammatory mediators, in particular myeloperoxidase (MPO) and serum amyloid A (SAA). This type of derangement of balance between two opposite forces makes HDL dysfunctional, i.e., unable to exert its "natural" vasculoprotective property. In this review, we summarized and critically analyzed the most significant findings linking HDL accessory proteins and AD. We also discuss the most convincing hypothesis explaining the mechanism by which an observed systemic occurrence may have repercussions in the brain.

Figure 1

Schematic representation of HDL “accessory proteins.” The most important members of the “family of accessory proteins” associated with HDL and object of the present review are as follows: (1) myeloperoxidase (MPO); (2) serum amyloid A (SAA); (3) lipoprotein phospholipase A2 (Lp-PLA2); (4) glutathione peroxidase-3 (GPx-3) and (5) PON3.

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].