Low density lipoprotein (LDL) particles are a class of cholesterol transporter, carrying cholesterol out from the liver where it is manufactured to the rest of the body via the bloodstream. LDL and its cargo can become oxidized as a result of interactions with the variety of oxidizing molecules produced in the normal operation of metabolism. This oxidized LDL is toxic and places stress upon cells in the blood vessel walls that encounter it. The level of oxidation increases globally with age, one of the known issues in an aged metabolism, and as a consequence there are more oxidized LDL particles and oxidized cholesterol molecules to cause problems in the vasculature. The research community is largely focused the role of oxidized LDL and oxidized cholesterol in the onset and progression of atherosclerosis, meaning the damage done to vascular endothelium that leads to excess accumulations of cholesterol, dysfunction in the macrophage cells drawn to attempt a repair, and the growth of an atherosclerotic plaque. There are other downstream consequences, however.
In today's open access review, researchers largely skate over the topic of atherosclerosis to discuss how oxidized LDL particles can contribute to vascular dementia. This is a matter of inflammation, endothelial dysfunction, and blood-brain barrier compromise in the microvasculature of the brain, issues distinct from the atherosclerotic plaque that forms in large arteries. At the high level, we might envisage the vasculature in the brain as a transformer that converts the biochemical issue of too many oxidizing molecules into chronic inflammation and related dysfunctions in brain tissues. Oxidative stress, mitochondrial dysfunction, and unresolved inflammatory signaling all circle round one another in aging, feeding into one another and downstream issues. It remains to be seen as to what the best points of intervention are, but clearing senescent cells and fixing mitochondrial dysfunction seem the best starting points at the present time.
Converging evidence indicates that the interplay of aging, LDL, and especially oxidized LDL (oxLDL) is a critical driver of cerebrovascular injury underlying vascular cognitive impairment and dementia (VCID). Epidemiological studies have demonstrated that midlife hypercholesterolemia is associated with an increased risk of dementia, with each ∼1 mmol/L rise in LDL levels linked to an estimated 8% higher incidence of all-cause dementia. Mechanistically, atherosclerosis-prone conditions like high LDL promote intracranial arterial disease that compromises cerebral perfusion and precipitates ischemic injury. Beyond large vessels, cholesterol and its oxidized derivatives can accumulate in the cerebral microvasculature, inciting local inflammation and neurodegeneration.
In the aging brain, these processes are compounded by an intrinsically fragile vasculature, establishing a strong case that aging, LDL, and oxLDL must be studied synergistically in the context of brain microvascular health and VCID pathogenesis. OxLDL emerges as a particularly deleterious player within the neurovascular unit (NVU). Once native LDL particles undergo oxidation, they trigger endothelial dysfunction more potently than native LDL. OxLDL engages endothelial cells to upregulate adhesion molecules and pro-inflammatory pathways, while directly degrading the integrity of the endothelial barrier. This damage to the blood-brain barrier (BBB) permits leakage of neurotoxic blood-derived factors into the brain parenchyma, exacerbating oxidative stress and inflammation within brain tissue.
Indeed, oxLDL creates a vicious cycle: it is readily taken up by macrophages and brain glia, generating foam cells and further reactive oxygen species (ROS) and cytokine release. The result is chronic neurovascular inflammation, reduced nitric oxide bioavailability (impairing vasodilation), and breakdown of microvascular structure, changes that manifest as small vessel disease, microhemorrhages, and ultimately cognitive impairment. Thus, aging-related oxidative stress and oxLDL together destabilize the BBB and cerebral perfusion, linking peripheral dyslipidemia to the hallmark microvascular lesions of VCID.
View the full article at FightAging
