Cao Chuanhai, Cirrito John R, Lin Xiaoyang, Wang Li, Verges Deborah K, Dickson Alexander, Mamcarz Malgorzata, Zhang Chi, Mori Takashi, Arendash Gary W, Holtzman David M, Potter Huntington
The Byrd Alzheimer's Center & Research Institute, Tampa, FL, USA.
J Alzheimers Dis. 2009;17(3):681-97. doi: 10.3233/JAD-2009-1071.
Recent epidemiologic studies suggest that caffeine may be protective against Alzheimer's disease (AD). Supportive of this premise, our previous studies have shown that moderate caffeine administration protects/restores cognitive function and suppresses brain amyloid-beta (Abeta) production in AD transgenic mice. In the present study, we report that acute caffeine administration to both young adult and aged AD transgenic mice rapidly reduces Abeta levels in both brain interstitial fluid and plasma without affecting Abeta elimination. Long-term oral caffeine treatment to aged AD mice provided not only sustained reductions in plasma Abeta, but also decreases in both soluble and deposited Abeta in hippocampus and cortex. Irrespective of caffeine treatment, plasma Abeta levels did not correlate with brain Abeta levels or with cognitive performance in individual aged AD mice. Although higher plasma caffeine levels were strongly associated with lower plasma Abeta1-40 levels in aged AD mice, plasma caffeine levels were also not linked to cognitive performance. Plasma caffeine and theophylline levels were tightly correlated, both being associated with reduced inflammatory cytokine levels in hippocampus. Our conclusion is two-fold: first, that both plasma and brain Abeta levels are reduced by acute or chronic caffeine administration in several AD transgenic lines and ages, indicating a therapeutic value of caffeine against AD; and second, that plasma Abeta levels are not an accurate index of brain Abeta levels/deposition or cognitive performance in aged AD mice.
近期的流行病学研究表明,咖啡因可能对阿尔茨海默病(AD)具有保护作用。支持这一前提的是,我们之前的研究表明,适度给予咖啡因可保护/恢复AD转基因小鼠的认知功能,并抑制其脑内β-淀粉样蛋白(Aβ)的产生。在本研究中,我们报告称,对年轻成年和老年AD转基因小鼠急性给予咖啡因可迅速降低脑间质液和血浆中的Aβ水平,而不影响Aβ的清除。对老年AD小鼠进行长期口服咖啡因治疗,不仅能持续降低血浆Aβ水平,还能减少海马体和皮质中可溶性和沉积性Aβ的含量。无论是否进行咖啡因治疗,老年AD小鼠个体的血浆Aβ水平与脑内Aβ水平或认知表现均无相关性。虽然老年AD小鼠中较高的血浆咖啡因水平与较低的血浆Aβ1-40水平密切相关,但血浆咖啡因水平也与认知表现无关。血浆咖啡因和茶碱水平紧密相关,二者均与海马体中炎症细胞因子水平降低有关。我们的结论有两点:第一,在多个AD转基因品系和不同年龄段中,急性或慢性给予咖啡因均可降低血浆和脑内的Aβ水平,表明咖啡因对AD具有治疗价值;第二,血浆Aβ水平并非老年AD小鼠脑内Aβ水平/沉积或认知表现的准确指标。