Caffeine Reverses Cognitive Impairment and Decreases Brain Amyloid-β Levels in Aged Alzheimer's Disease Mice
Caffeine Reverses Cognitive Impairment and Decreases Brain Amyloid-β Levels in Aged Alzheimer's Disease Mice
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DOI：
10.3233/jad-2009-1087
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发表时间：
2009-07-01
影响因子：
4
通讯作者：
Potter, Huntington
中科院分区：
文献类型：
--
作者：
Arendash, Gary W.;Mori, Takashi;Potter, Huntington
我们最近已经证明，给予中等水平的咖啡因摄入量（相当于人类每天5杯咖啡）的阿尔茨海默病（AD）转基因小鼠可以防止其他某些认知障碍的发展，并且由于抑制β-分泌酶（BACE 1）和早老素1（PS1）/γ-分泌酶表达而降低了海马淀粉样蛋白β（A β）水平。为了确定咖啡因摄入是否可以在已经表现出认知障碍的“老年”APPsw小鼠中具有有益效果，我们在工作记忆受损的18-19个月大的APPsw小鼠的饮用水中给予咖啡因。在咖啡因治疗4-5周时，与对照转基因小鼠的持续损害相比，给予咖啡因（Tg/Caff）的那些受损转基因小鼠表现出极大的上级工作记忆。此外，Tg/Caff小鼠在海马（向下箭头40%）和内嗅皮质（向下箭头46%）中的A β沉积显著减少，以及脑可溶性A β水平的相关降低。从机制上讲，有证据表明咖啡因对BACE 1的抑制涉及cRaf-1/NF κ B途径。我们还确定，在人体生理范围内的咖啡因浓度有效地降低SweAPP N2 a细胞中的活性和总糖原合成酶激酶3水平。即使预先存在大量A β负荷，老年APPsw小鼠也表现出记忆恢复和AD病理学逆转，表明咖啡因在已建立的AD病例中的治疗潜力。
We have recently shown that Alzheimer's disease ( AD) transgenic mice given a moderate level of caffeine intake ( the human equivalent of 5 cups of coffee per day) are protected from development of otherwise certain cognitive impairment and have decreased hippocampal amyloid-beta (A beta) levels due to suppression of both beta-secretase ( BACE1) and presenilin 1 ( PS1)/gamma-secretase expression. To determine if caffeine intake can have beneficial effects in "aged" APPsw mice already demonstrating cognitive impairment, we administered caffeine in the drinking water of 18-19 month old APPsw mice that were impaired in working memory. At 4-5 weeks into caffeine treatment, those impaired transgenic mice given caffeine (Tg/Caff) exhibited vastly superior working memory compared to the continuing impairment of control transgenic mice. In addition, Tg/Caff mice had substantially reduced A beta deposition in hippocampus (down arrow 40%) and entorhinal cortex (down arrow 46%), as well as correlated decreases in brain soluble A beta levels. Mechanistically, evidence is provided that caffeine suppression of BACE1 involves the cRaf-1/NF kappa B pathway. We also determined that caffeine concentrations within human physiological range effectively reduce active and total glycogen synthase kinase 3 levels in SweAPP N2a cells. Even with pre-existing and substantial A beta burden, aged APPsw mice exhibited memory restoration and reversal of AD pathology, suggesting a treatment potential of caffeine in cases of established AD.