Wostyn Peter, Audenaert Kurt, De Deyn Peter Paul
Department of Psychiatry, PC Sint-Amandus, Reigerlostraat 10, 8730 Beernem, Belgium.
Perspect Medicin Chem. 2011 Feb 23;5:11-7. doi: 10.4137/PMC.S6509.
Alzheimer's disease is known to be the most common form of dementia in the elderly. It is clinically characterized by impairment of cognitive functions, as well as changes in personality, behavioral disturbances and an impaired ability to perform activities of daily living. To date, there are no effective ways to cure or reverse the disease. Genetic studies of early-onset familial Alzheimer's disease cases revealed causative mutations in the genes encoding β-amyloid precursor protein and the γ-secretase-complex components presenilin-1 and presenilin-2, supporting an important role of β-amyloid in the pathogenesis of Alzheimer's disease. Compromised function of the choroid plexus and defective cerebrospinal fluid production and turnover, with diminished clearance of β-amyloid, may play an important role in late-onset forms of Alzheimer's disease. If reduced cerebrospinal fluid turnover is a risk factor for Alzheimer's disease, then therapeutic strategies to improve cerebrospinal fluid flow are reasonable. However, the role of deficient cerebrospinal fluid dynamics in Alzheimer's disease and the relevance of choroidal proteins as potential therapeutic targets to enhance cerebrospinal fluid turnover have received relatively little research attention. In this paper, we discuss several choroidal proteins, such as Na(+)-K(+) ATPase, carbonic anhydrase, and aquaporin 1, that may be targets for pharmacological up-regulation of cerebrospinal fluid formation. The search for potentially beneficial drugs useful to ameliorate Alzheimer's disease by facilitating cerebrospinal fluid production and turnover may be an important area for future research. However, the ultimate utility of such modulators in the management of Alzheimer's disease remains to be determined. Here, we hypothesize that caffeine, the most commonly used psychoactive drug in the world, may be an attractive therapeutic candidate for treatment of Alzheimer's disease since long-term caffeine consumption may augment cerebrospinal fluid production. Other potential mechanisms of cognitive protection by caffeine have been suggested by recent studies.
已知阿尔茨海默病是老年人中最常见的痴呆形式。其临床特征为认知功能受损、人格改变、行为障碍以及日常生活活动能力受损。迄今为止，尚无有效的方法治愈或逆转该疾病。早发性家族性阿尔茨海默病病例的基因研究揭示了编码β-淀粉样前体蛋白以及γ-分泌酶复合物成分早老素-1和早老素-2的基因中的致病突变，这支持了β-淀粉样蛋白在阿尔茨海默病发病机制中的重要作用。脉络丛功能受损以及脑脊液生成和周转存在缺陷，伴有β-淀粉样蛋白清除减少，可能在晚发性阿尔茨海默病中起重要作用。如果脑脊液周转减少是阿尔茨海默病的一个危险因素，那么改善脑脊液流动的治疗策略是合理的。然而，脑脊液动力学不足在阿尔茨海默病中的作用以及脉络丛蛋白作为增强脑脊液周转的潜在治疗靶点的相关性相对较少受到研究关注。在本文中，我们讨论了几种脉络丛蛋白，如钠钾ATP酶（Na(+)-K(+) ATPase）、碳酸酐酶和水通道蛋白1，它们可能是脑脊液生成的药理学上调靶点。通过促进脑脊液生成和周转来寻找对改善阿尔茨海默病有益的潜在药物可能是未来研究的一个重要领域。然而，此类调节剂在阿尔茨海默病管理中的最终效用仍有待确定。在此，我们假设咖啡因作为世界上最常用的精神活性药物，可能是治疗阿尔茨海默病的一个有吸引力的治疗候选药物，因为长期摄入咖啡因可能会增加脑脊液生成。近期研究还提出了咖啡因认知保护的其他潜在机制。
