Elevated cholesterol in mid-life has been associated with increased risk of
dementia in later life. We have previously shown that
low density lipoprotein (
LDL) is more oxidised in the plasma of
dementia patients although total
cholesterol levels remained unchanged. Increased systemic oxidative modification (
oxLDL) and nitration is also observed during
hypercholesterolemia. We have investigated the hypothesis that disruption of blood brain barrier (BBB) function by
oxLDL and their
lipids may increase risk of neurodegeneration in later life and that
statin intervention can mitigate the effects of hyperlipidaemia in mid-life.
LDL isolated from
statin-naïve hypercholesterolaemic subjects had higher mobility by
agarose gel electrophoresis (Rf;0.53±0.06) and
8-isoprostane F2α concentration (43.5±8.42pg/ml) compared to control subjects (Rf; 0.46±0.05 and 24.2±5.37pg/ml respectively; p<0.05). Compared to HMVEC treatment with the
LDL-
lipids (5μM) from normolipidaemic subjects,
LDL-
lipids from hypercholesterolaemic subjects increased barrier permeability (103.4±12.5 Ωcm2 v 66.7±7.3 Ωcm2,P<0.01) and decreased cellular
glutathione levels (18.5nmol/mg v 12.3nmol/mg) compared to untreated cells (26.2±3.6nmol/mg).
LDL-
lipids isolated from normolipidaemic subjects shows reduced risk to damage a BBB model compared with
LDL-
lipids from hypercholesterolaemic subjects. Moreover, a three month
statin-intervention reduced the propensity for
LDL-
lipids from subjects with hyperlipidaemia to damage HMVEC. Post-
statin treatment the cytotoxic and pro-inflammatory effects of
LDL lipids disappeared. These data support the hypothesis that in vivo intervention with
statins modifies
LDL lipid oxidation, exerting a protective effect against in microvascular damage independent of
cholesterol concentration.