Apolipoprotein E Protects against Neuropathology Induced by a High-Fat Diet and Maintains the Integrity of the Blood-Brain Barrier during Aging

Abstract

SUMMARY: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 (BBB) functioning, in the brains of apolipoprotein E (apoE)-knockout mice, but not of C57Bl/6 control mice. Using sodium fluorescein as a marker for the permeability of the BBB, we found additional support for age-related disturbances of BBB function in apoE-knockout mice. Behavioral analysis of apoE-knockout mice compared with C57Bl/6 mice indicated that they were also less efficient in acquiring the spatial Morris water maze task. Furthermore, apoE-knockout mice are known to develop severe atherosclerosis, which is exacerbated with a high-fat diet. We therefore compared 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 disturbances. These results indicate for the first time that apoE plays an essential role in the maintenance of the integrity of the BBB during aging and that 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 integrity of the BBB may be the mechanism by which apoE affects the progression of neurodegeneration, as seen in Alzheimer's disease. (Lab Invest 2001, 81:953-960).A polipoprotein E (apoE) is synthesized in almost all cell types and throughout the body. Within the brain, astrocytes are the predominant source of apoE (Pitas et al, 1987). It is thought that apoE functions by mediating neuronal repair and/or remodeling during development and during regeneration after injury to the central nervous system by mediating the distribution of lipids, predominantly cholesterol and phospholipids (Nathan et al, 1994).Three common human isoforms of apoE exist: E2, E3, and E4. ApoE4 is now a well-established risk factor for the development of Alzheimer's disease (AD) (Corder et al, 1993;Saunders et al, 1993). ApoE4 has also been associated with other neurological diseases, including vascular dementia and a poor clinical outcome in patients after stroke and head injury (Nicoll et al, 1995;Slooter et al, 1997). The mechanism by which apoE4 affects the process of neurodegeneration, however, is largely unknown.Mice deficient in apoE display disturbances in learning and memory function as well as in long-term potentiation (Krugers et al, 1997;Krzywkowski et al, 1999;Oitzl et al, 1997;Veinbergs and Masliah, 1999). They display several neuropathologic alterations, including a loss of synapses with increasing age, cytoskeletal alterations (Masliah et al, 1995), and a reduced activity of choline acetyltransferase (Gordon et al, 1995). In addition, they show an impaired response to ischemic, traumatic, and excitotoxic lesions (Chen et al, 1997;Laskowitz et al, 1997). On the contrary, a few studies report neit...

Genetic Restoration of Plasma ApoE Improves Cognition and Partially Restores Synaptic Defects in ApoE-Deficient Mice

“…It has been shown that female ApoE KO mice display greater cognitive impairment than male ApoE KO mice (Raber et al, 1998), a result we have replicated here. Importantly, the impairment in the female ApoE KO mice was completely rescued in the female bEKO mice.…”

“…In peripheral tissues, ApoE is expressed primarily by the liver and released into the blood. In the brain, ApoE is expressed primarily by astrocytes, but can also be expressed by neurons and microglia during cell stress or injury (Pitas et al, 1987;Stone et al, 1997;. Typically, ApoE cannot pass through the BBB (Björkhem et al, 1998); thus, the two pools of ApoE are largely separate.…”

“…In addition to vascular changes, ApoE knock-out mice exhibit an age-dependent breakdown of the BBB, which correlates with behavioral impairments (Mulder et al, 2001;Bell et al, 2012). This breakdown can be partially restored with a bone marrow transplant from wild-type mice, which introduces ApoEexpressing leukocytes and restores a small amount (ϳ3%) of ApoE to the plasma (Hafezi-Moghadam et al, 2007).…”

Cerebral Oxidative Stress and Microvasculature Defects in TNF-α Expressing Transgenic and Porphyromonas gingivalis-Infected ApoE–/– Mice

“…From animal models, proinflammatory cytokines, such as TNF-α, are known to disturb inter-endothelial cell-cell connections and thereby cause BBB permeability [19]. This makes TNF-α transgenic mice [31] and ApoE -/-mice brains [27,29,30], ideal test models to investigate if they share common oxidative stress from an intrinsic biological (proinflammatory cytokine) stressor. We first established that the leaky BBB was restricted to the cerebellum and not the cerebral microvessels in both TNF-α transgenic and ApoE -/-mice brains.…”

“…The genetically modified apolipoprotein E knockout (ApoE -/-) mouse is a good example, in order to determine the effects of peripheral infection on a host undergoing high intrinsic stress, due to the constitutive expression of the proinflammatory cytokine, TNF-α [21,22], lipid peroxidation [23], impaired immuno-modulatory function in macrophages and innate/adaptive immune responses [24][25][26]; and impaired cerebellar microvessels [27][28][29][30].…”