Impairment of the blood-nerve and blood-brain barriers in apolipoprotein e knockout mice

Apolipoprotein E (apoE) is well characterized as a plasma lipoprotein involved in lipid and cholesterol metabolism. Recent studies implicating apoE in Alzheimer's disease and successful recovery from neurological injury have stimulated much interest in the functions of apoE within the brain. To explore the functions of apoE within the nervous system, we examined apoE knockout (KO) mice. Previously, we showed that apoE KO mice have a delayed response to noxious thermal stimuli associated with a loss and abnormal morphology of unmyelinated fibers in the sciatic nerve. From these data, we hypothesized that apoE KO mice could have an impaired blood-nerve barrier (BNB). In this report, we demonstrate functionally impaired blood-nerve and blood-brain barriers (BBB) in apoE KO mice using immunofluorescent detection of serum protein leakage into nervous tissue as a diagnostic for decreased BNB and BBB integrity. Extensive extravasation of serum immunoglobulin G (IgG) is detected in the sciatic nerve, spinal cord, and cerebellum of apoE KO but not WT mice. In a subpopulation of apoE KO mice, IgG also extravasates into discrete cortical and subcortical locations, including hippocampus. Loss of BBB integrity was additionally confirmed by the ability of exogenously supplied Evans blue dye to penetrate the BBB and to colocalize with IgG immunoreactivity in CNS tissue. These observations support a role for apoE in maintaining the integrity of the BNB/BBB and suggest a novel relationship between apoE and neural injury.