Chen Xuesong, Gawryluk Jeremy W, Wagener John F, Ghribi Othman, Geiger Jonathan D
Department of Pharmacology, Physiology and Therapeutics, School of Medicine and Health Sciences, University of North Dakota, 501 N, Columbia Rd,, Grand Forks, ND 58203, USA.
J Neuroinflammation. 2008 Apr 3;5:12. doi: 10.1186/1742-2094-5-12.
High levels of serum cholesterol and disruptions of the blood brain barrier (BBB) have all been implicated as underlying mechanisms in the pathogenesis of Alzheimer's disease. Results from studies conducted in animals and humans suggest that caffeine might be protective against Alzheimer's disease but by poorly understood mechanisms. Using rabbits fed a cholesterol-enriched diet, we tested our hypothesis that chronic ingestion of caffeine protects against high cholesterol diet-induced disruptions of the BBB. New Zealand rabbits were fed a 2% cholesterol-enriched diet, and 3 mg caffeine was administered daily in drinking water for 12 weeks. Total cholesterol and caffeine concentrations from blood were measured. Olfactory bulbs (and for some studies hippocampus and cerebral cortex as well) were evaluated for BBB leakage, BBB tight junction protein expression levels, activation of astrocytes, and microglia density using histological, immunostaining and immunoblotting techniques. We found that caffeine blocked high cholesterol diet-induced increases in extravasation of IgG and fibrinogen, increases in leakage of Evan's blue dye, decreases in levels of the tight junction proteins occludin and ZO-1, increases in astrocytes activation and microglia density where IgG extravasation was present. Chronic ingestion of caffeine protects against high cholesterol diet-induced increases in disruptions of the BBB, and caffeine and drugs similar to caffeine might be useful in the treatment of Alzheimer's disease.
血清胆固醇水平升高和血脑屏障（BBB）破坏均被认为是阿尔茨海默病发病机制的潜在因素。在动物和人类中进行的研究结果表明，咖啡因可能对阿尔茨海默病具有保护作用，但其作用机制尚不清楚。我们以喂食高胆固醇饮食的兔子为实验对象，验证了慢性摄入咖啡因可预防高胆固醇饮食诱导的血脑屏障破坏这一假设。给新西兰兔喂食含2%胆固醇的饮食，并在饮水中每日给予3毫克咖啡因，持续12周。测量血液中的总胆固醇和咖啡因浓度。使用组织学、免疫染色和免疫印迹技术，评估嗅球（部分研究还包括海马体和大脑皮层）的血脑屏障渗漏、血脑屏障紧密连接蛋白表达水平、星形胶质细胞活化和小胶质细胞密度。我们发现，咖啡因可阻止高胆固醇饮食诱导的IgG和纤维蛋白原外渗增加、伊文思蓝染料渗漏增加、紧密连接蛋白occludin和ZO-1水平降低、星形胶质细胞活化增加以及存在IgG外渗部位的小胶质细胞密度增加。慢性摄入咖啡因可预防高胆固醇饮食诱导的血脑屏障破坏增加，咖啡因及类似咖啡因的药物可能对阿尔茨海默病的治疗有用。
