Apolipoprotein E protects against neuropathology induced by a high-fat diet and maintains the integrity of the blood-brain barrier during aging

The present study provides evidence that chronic intake of a high-fat diet induces a dramatic extravasation of immunoglobulins, indicating alterations in blood-brain barrier (SBB) functioning, in the brains of apolipoprotein E (apoE)-knockout mice, but not of C57B1/6 control mice. Using sodium fluor escein as a marker for the permeability of the BBB, we found additional sup port for age-related disturbances of BBB function in apoE-knockout mice. Be havioral analysis of apoE-knockout mice compared with C57B1/6 mice indicate d that they were also less efficient in acquiring the spatial Morris water maze task. Furthermore, apoE-knockout mice are known to develop severe athe rosclerosis, which is exacerbated with a high-fat diet. We therefore compar ed the apoE-knockout mice with the apoE3-Leiden transgenic mice, which are known to develop atherosclerosis. However, apoE3-Leiden mice that were kept on a high-fat, high-cholesterol diet and that developed atherosclerosis to an extent similar to the apoE-knockout mice, showed no signs of BBB distur bances. These results indicate for the first time that apoE plays an essent ial role in the maintenance of the integrity of the BBB during aging and th at it protects the brain from neuropathology induced by a high-fat diet. We therefore hypothesize that the role of apoE in the maintenance of the inte grity of the BBB may be the mechanism by which apoE affects the progression of neurodegeneration, as seen in Alzheimer's disease.