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Mouse models may provide new insight into...

http://www.cnophol.com 2009-8-7 14:54:57 中华眼科在线

Mouse models may provide new insight into the relation between cholesterol and age related macular degeneration

【关键词】  age,related,macular,degeneration;,mouse,models

With the goal of preventing vision loss from this disease, it is important to identify modifiable risk factors that may be targets for intervention

Keywords: age related macular degeneration; mouse models

Age related macular degeneration (AMD) is the leading cause of severe vision loss among the elderly in the United States, Europe, and Australia. However, the cause of this blinding disease remains a topic of active investigation. Most agree the pathogenesis of AMD is multifactorial and that it results from the interaction of genetic, environmental and ageing effects. Evidence from population based studies has supported a role for heredity in the pathogenesis of AMD. Recent studies have identified a polymorphism in the gene for complement factor H which may be present in up to half of all white AMD patients.14 However, polymorphisms in this gene are also frequently found in Japanese5 and Chinese6 populations, where AMD infrequently causes vision loss. Clearly, development of AMD depends on the interaction of genetic background with other, presumably environmental, factors.

With the goal of preventing vision loss from this disease, it is important to identify modifiable risk factors that may be targets for intervention. Some, but not all, epidemiological studies have identified an association between cardiovascular disease risk and AMD.7 Cigarette smoking, a well recognised risk factor for cardiovascular disease, is the most consistently demonstrated modifiable risk factor contributing to AMD,8 and its role in complement activation has been considered supportive evidence of the part played by complement factor H mutations.3 Recent case-control9 and prospective10 studies have identified elevated C reactive protein, an inflammatory biomarker associated with cardiovascular disease, as a risk factor for AMD and AMD progression. Systemic hypertension has been associated with neovascular AMD11 and a poorer response to laser therapy for choroidal neovascularisation (CNV) in patients with AMD.12 Some studies have found an association between markers of systemic atherosclerosis and AMD,13,14 but other large population based studies have found no consistent association.11,15 Increased dietary consumption of saturated fat,16,17 monounsaturated and polyunsaturated fat and vegetable fat17 and cholesterol16 has been associated with early and late AMD in various studies. Some recent studies have identified an association between use of cholesterol lowering medications, such as statins, and reduced risk of early or late AMD,1822 while others have found no such association.2325 Although total serum cholesterol has been associated with neovascular AMD in a large case-control study,26 many large population based studies have found no association.8,27 Some studies have suggested an association between different lipoprotein polymorphisms and risk of AMD, including apoE,28,29 apo B, and apo A1.30 Certainly the relation between cardiovascular risk factors, lipid metabolism, and AMD remains confusing.

The findings described in LDL receptor deficient mice may provide insight into the mechanism of early AMD

Insight into the role lipid metabolism has in the development of early AMD has come from the study of preclinical models. Although no murine model exists that exactly replicates the phenotype seen in human AMD, studies have shown that C57Bl/6 mice fed a high fat diet and briefly exposed to blue-green light develop basal laminar deposits,31 a histological feature of human eyes with AMD.32 Mice with null mutations in apoE have shown basal linear deposits and thickened Bruch’s membranes, similar to findings in human eyes with AMD.33,34 However, neither of these models develops choroidal neovascularisation or geographic atrophy, the stages of AMD associated with vision loss in patients, limiting our understanding of the mechanisms responsible for these sight threatening complications.

In this issue of the BJO (p 1627), Rudolf and colleagues present novel information about mice with a null mutation for the low density lipoprotein (LDL) receptor, which have been studied as a murine model of atherosclerosis. After receiving a high fat diet, LDL receptor deficient mice develop membrane bound translucent particles within a significantly thickened Bruch’s membrane, while control mice with normal LDL receptors show no Bruch’s membrane abnormalities. The membrane bound translucent particles observed in the LDL receptor deficient mice resemble vesicles observed in histological sections of basal linear deposits and large drusen, findings specific for early AMD.35 Although plasma cholesterol is significantly elevated in LDL receptor deficient mice fed both normal and high fat diets, it is not clear from the present work that the changes in Bruch’s membrane in LDL receptor deficient mice derive from plasma cholesterol rather than from an intraocular source.36 Further ultrastructural analysis of the lipid composition of Bruch’s membrane in LDL receptor deficient mice, using previously described methods to preserve neutral lipids,36 may provide insight into whether these deposits result from elevated plasma lipid levels or an intraocular source. Such information may clarify the discrepancies noted between plasma lipid abnormalities and risk of AMD in epidemiological studies.

Of interest, the authors demonstrate immunohistochemical reactivity for vascular endothelial growth factor (VEGF) in the basal retinal pigment epithelial (RPE) cells, the outer plexiform layer, and the photoreceptor inner segments of LDL receptor deficient mice, which increased after the mice received a high fat diet. The authors state that no spontaneous CNV was observed in the mice studied despite high levels of VEGF expression. However, the mice in this study were investigated at 4 months of age. It will be interesting to observe LDL receptor deficient mice at senescent ages to determine if the changes described in Bruch’s membrane progress with advanced age or are accompanied by the development of CNV or RPE atrophy. Other mutant mice with phenotypes similar to human AMD develop fundus and histological changes only after the age of 9 months, with geographic atrophy and CNV developing only after 16 months and 18 months of age, respectively.37

Even in the absence of correlates of late AMD, the findings described in LDL receptor deficient mice may provide insight into the mechanism of early AMD. The fact that the mice develop abnormally thickened Bruch’s membranes, similar to early AMD, and demonstrate VEGF upregulation suggests that ischaemia or oxidative stress occurs even in early stages of AMD, perhaps as a result of compromised diffusion from the choriocapillaris to the outer retina. LDL receptor deficient mice will serve as a useful model of early AMD and may allow investigators to determine the part abnormalities of cholesterol metabolism may play in its pathogenesis. Whether or not deficiencies in the LDL receptor are associated with AMD in humans, the ocular phenotype of LDL receptor deficient mice described in the present work should encourage investigators to study murine models of atherosclerosis with careful attention to the eyes.

ACKNOWLEDGEMENTS

This work was supported by a Career Development Award from Research to Prevent Blindness, New York, New York; grants EY00415 and EY02162 from the National Eye Institute, Bethesda, Maryland; and grants from the Bernard A Newcomb Macular Degeneration Fund and That Man May See, Inc, San Francisco, California, and the Foundation Fighting Blindness, Owings Mills, Maryland, USA.

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