高级糖化终产物诱导阿尔茨海默病样病理改变及相关机制研究
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摘要
[背景]
过度磷酸化的tau蛋白和β-淀粉样多肽((3-amyloid, Aβ)的聚积是阿尔茨海默病(alzheimer disease, AD)的两大特征性病理改变—神经原纤维缠结(neurofibrillary tangles, NFTs)和老年斑(senile plaques, SPs)的主要成分。高级糖化终产物(advanced glycation endproducts, AGEs)是蛋白质的氨基与还原糖及其衍生物的羰基发生非酶促反应后生成的不可逆的糖化产物。随着年龄的增加,AGEs的生成会逐渐增多,特别是体内血糖升高时如糖尿病患者,AGEs会显著增加。研究发现,与同龄对照组相比,AD患者或模型脑脊液和血液中AGEs水平明显升高；免疫学的证据也表明AGEs与神经原纤维缠结和老年斑共定位。以上研究提示AGEs可能是导致糖尿病患者和老年人口AD发生危险性升高的重要原因之一,但AGEs如何影响tau蛋白磷酸化、Aβ代谢和脑功能及其机制,迄今为止尚不清楚。早期降低AGEs的水平是否能逆转拟AD模型鼠的AD样病理改变和空间学习记忆能力的损伤,目前也未见报道。
[目的]
探讨AGEs对tau蛋白磷酸化和Aβ代谢的影响及机制；研究AGEs对大鼠空间记忆能力的影响以及早期干预拟AD模型的AGEs生成能否预防脑结构和功能的损伤。
[方法]
体外研究：我们采用合成的AGEs处理SK-N-SH细胞和原代海马神经元,并用高级糖化终产物受体(receptor for advanced glycation endproducts, RAGE)抗体、糖原合酶激酶-3(glycogen synthase kinase-3, GSK-3)抑制剂(SB216763, LiCl)、细胞外信号调节激酶1和2(Extracellular Signal Regulated Kinase 1/2, Erk1/2)抑制剂(PD98059)或p38抑制剂(SB202190)与AGEs共处理。
体内研究：我们采用立体定位注射的方法对SD大鼠双侧海马注射AGEs,合并注射RAGE抗体或GSK-3抑制剂。为研究早期干预AGEs对AD的影响,我们选用6月龄拟AD模型Tg2576小鼠,连续3个月皮下注射氨基胍(aminoguanidine, AG)或生理盐水(normal saline, NS)。
采用免疫印迹或免疫组织化学检测tau蛋白磷酸化、蛋白激酶或磷酸酯酶的活性依赖性修饰以及突触蛋白的表达水平；采用酶联免疫吸附法ELISA检测Ap的水平；采用免疫共沉淀检测Ap的的糖化水平；采用长时程电位增强(long term potentiation, LTP)技术检测突触可塑性；采用转染绿色荧光蛋白检测原代海马神经元树突棘的数目和形态；采用水迷宫试验检测大鼠的空间记忆功能。
[结果]
1) AGEs可通过RAGE/GSK-3通路诱导tau蛋白过度磷酸化。
AGEs可诱导SK-N-SH细胞、原代海马神经元和SD大鼠的tau蛋白过度磷酸化。为了探讨AGEs诱导tau蛋白过度磷酸化的机制,我们用AGEs(最佳浓度50μg/ml,最佳时间24h)处理SK-N-SH细胞,发现AGEs在诱导tau蛋白过度磷酸化的同时,伴随有RAGE mRNA和蛋白水平的升高、Akt活性的抑制以及蛋白激酶(GSK-3、Erk1/2和p38)活性的激活,而其它蛋白激酶,如c-Jun氨基末端激酶(c-Jun N-terminal kinase, JNK),钙调蛋白激酶Ⅱ(calcium calmodulin-dependent protein kinaseⅡ, CaMKⅡ),蛋白激酶A调节亚基(regulary unit of protein kinase A Iα, PKA RIα)和PKA RⅡβ,以及磷酸酯酶2A (protein phosphatases 2A, PP2A)的活性无明显变化。为了进一步确定以上有活性改变的蛋白分子在AGEs诱导的tau蛋白过度磷酸化中的作用,我们采用RAGE抗体和相关蛋白激酶抑制剂与AGEs共处理,结果发现当共处理RAGE抗体或GSK-3抑制剂时可有效逆转AGEs诱导的tau蛋白过度磷酸化,而同时抑制Erk1/2或p38无明显变化,提示RAGE和GSK-3可能在AGEs诱导的tau蛋白过度磷酸化中起重要作用。
2) AGEs损伤大鼠空间记忆能力,其机制涉及AGEs通过RAGE/GSK-3通路导致tau蛋白过度磷酸化、LTP抑制、突触蛋白下降、树突棘减少。
我们发现,注射AGEs损伤SD大鼠空间记忆能力。为了探讨相关机制,我们检测了与空间记忆相关的指标,如tau蛋白磷酸化、LTP和突触相关蛋白。发现注射AGEs可导致tau蛋白过度磷酸化、LTP抑制、多种突触蛋白(尤其是突触后蛋白PSD95、PSD93、NR2A和NR2B)水平降低。同时,伴随有RAGE水平升高、AKt抑制和GSK-3激活。为进一步研究RAGE和GSK-3的作用,我们采用了RAGE抗体或GSK-3抑制剂与AGEs一起海马定位注射,结果发现同时阻断RAGE或抑制GSK-3可显著改善AGEs诱导的大鼠空间记忆障碍,伴随tau蛋白磷酸化、LTP和突触蛋白水平的恢复。
3)早期阻止AGEs聚积可有效预防拟AD模型空间学习记忆损伤,伴随Aβ和tau蛋白磷酸化水平降低、突触蛋白含量恢复。
我们选择从6月龄小鼠开始皮下注射氨基胍AG。对照组注射同体积生理盐水NS。3个月后,发现给予AG可明显抑制AGEs的生成；同时,AG干预组小鼠的空间学习记忆能力改善、tau蛋白在Thr231和Ser396位点磷酸化水平降低、突触蛋白和相关记忆分子水平升高、Aβ水平明显降低。用免疫共沉淀方法检测AGEs与Aβ的相互作用,发现Ap可明显被AGE化。
[结论]
1) AGEs可通过RAGE/GSK-3信号通路诱导tau蛋白过度磷酸化。
2)Aβ在体内可发生糖化,糖化能促进Aβ的聚积。
3) AGEs可通过RAGE/GSK-3信号通路诱导大鼠空间记忆能力的损伤,早期抑制AGEs生成可逆转拟AD模型Tg2576小鼠的空间学习记忆的损伤。
Background The hallmark lesions observed in Alzheimer disease (AD) brain is the formation of numerous neurofibrillary tangles (NFTs) and senile plaques (SPs), which are respectively composed of the hyperphosphorylated tau and (3-amyloid (Aβ). The advanced glycation endproducts (AGEs) are produced from a complex nonenzymatic multistep reaction of reducing sugars or dicarboneyl compounds, such as glyoxal and methylglyoxal, with the amino groups of proteins, especially the N-terminal amino groups and side chains of lysine and arginine. AGEs are elevated in the AD brains and the AGEs can stimulateβ-amyloid production and colocalize with NFTs and SPs, suggesting that AGEs play an important role in pathogenesis of AD. However, whether and how AGEs may cause AD-like tau hyperphosphorylation, whether elevated AGEs could induce spatial memory impairment, and whether early decreasing AGEs could reverse spatial memory defict of AD model are not reported.
Objective It was to investigate the effects of AGEs on tau phosphorlation, Aβmetabolism and spatial memory, and whether decreasing AGEs accumulation could prevent memory deficits and AD-like pathologies in Tg2576 mice.
Methods In vitro, we used exogenous AGEs to treat SK-N-SH cells and primary hippocampal neurons. RAGE antibody or inhibitors of GSK-3 (SB216763, LiC1), Erk1/2 (PD98059) and p38 (SB202190) were simultaneously co-incubated with AGEs. In vivo, we injected AGEs with or without RAGE antibody or LiCl into the hippocampus of SD rats. In order to study early inhibition of AGEs on AD model,6-m Tg2576 mice were used and subcutaneously injected with 0.9% normal saline (NS) or aminoguanidine (AG) for 3 m. Tau phosphorylation, protein kinases and phosphoesterase, synapse proteins were measured with western blotting or immunohischemistry. The level of A(3 and AGEs were measured with ELISA or dot blot. The interaction of Aβand AGEs was investigated with co-immunoprecipitation. Synapse plasticity was examined with long term potentiation (LTP). Spatial memory was investigated with Morris water maze.
Results
(1) AGEs could induce tau hyperphosphorylation through RAGE/GSK-3 pathway.
First, we found AGEs induced tau hyperphosphorylation in SK-N-SH cells, primary hippocampal neurons and SD rats. Then, to study the underlying mechanism, we used the optimal concentration of AGEs (50μg/ml) to treat SK-N-SH cells for the optimal time (24 h). We observed that, with AGEs-induced tau hyperphosphorylation, mRNA and protein level of RAGE (receptor for AGEs) were elevated, the activity of akt was inhibited, and GSK-3, p38 and Erk1/2 were activated. At the last, to further indentify the role of the above chanded proteins in AGEs-induced tau hyperphosphorylation, we used Co-incubation of RAGE antibody or GSK-3 inhibitor with AGE to treat cells. We found that only RAGE antibody and GSK-3 inhibitor could insignificantly reverse tau hyperphosphorylation induced by AGEs, suggesting AGEs could induce tau hyperphosphorylation through RAGE/GSK-3 pathway.
(2) AGEs could induce spatial memory deficit of SD rats, with tau hyperphosphorylation, inhibition of LTP, decline of synapse-related proteins through RAGE/GSK-3 pathway.
First, we found that AGEs induced spatial memory deficit of SD rats. Then, to explore the possible mechanism, we investigated memory-related markers. We found that, with the impairment of memory, tau was hyperphosphorylated, LTP was inhibited, and synaptic proteins, especially postsynaptic proteins, were decreased. Meanwhile, with the hyperphosphorylated tau, RAGE was elevated, akt was inhibited, and GSK-3 was activated. And then, to further study the underlying mechanism of memory deficit, rats were co-injected with AGEs plus RAGE antibody or GSK-3 inhibitor, and found that co-injection not only significantly improve tau hyperphosphorylation, inhibiton of LTP, and decrease of synaptic proteins, but also reverse AGEs-induced memory impairment.
(3) Early inhibiton of AGEs could revesrse memory deficit of AD model, which may be mediated by AGEs-induced decrease of A(3 production.
We selected 6-m mice to treate AG. Then,6-m Tg2576 mice were used and subcutaneously injected with normal saline (NS) or aminoguanidine (AG) for 3 m. We found that AG treatment could effectively inhibit the production of AGEs, and compared with age-matched groups injected with NS, decrease of AGEs significantly reverse memory deficit of Tg2576 mice, with decrese of tau hyperphosphorylation at site of Thr231 and Ser396, and increase of synaptic proteins. Meanwhile, after treatment of AG, production of Aβwas declined with the decreae of AGEs. To explore the possible mechanism of decrease of Aβ, we used co-immunoprecipitation to study the interaction of AGEs and Aβ, and found that Aβcould be glycated by AGEs.
Conclusion Our data reveal that AGEs can induce tau hyperphosphorylation and Aβoverproduction; AGEs cause impairments of spatial memory through RAGE-mediated GSK-3 activation; Early inhibiton of AGEs could reverse memory deficit in Tg2576 mice.
过度磷酸化的tau蛋白和β-淀粉样多肽((3-amyloid, Aβ)的聚积是阿尔茨海默病(alzheimer disease, AD)的两大特征性病理改变—神经原纤维缠结(neurofibrillary tangles, NFTs)和老年斑(senile plaques, SPs)的主要成分。高级糖化终产物(advanced glycation endproducts, AGEs)是蛋白质的氨基与还原糖及其衍生物的羰基发生非酶促反应后生成的不可逆的糖化产物。随着年龄的增加,AGEs的生成会逐渐增多,特别是体内血糖升高时如糖尿病患者,AGEs会显著增加。研究发现,与同龄对照组相比,AD患者或模型脑脊液和血液中AGEs水平明显升高；免疫学的证据也表明AGEs与神经原纤维缠结和老年斑共定位。以上研究提示AGEs可能是导致糖尿病患者和老年人口AD发生危险性升高的重要原因之一,但AGEs如何影响tau蛋白磷酸化、Aβ代谢和脑功能及其机制,迄今为止尚不清楚。早期降低AGEs的水平是否能逆转拟AD模型鼠的AD样病理改变和空间学习记忆能力的损伤,目前也未见报道。
[目的]
探讨AGEs对tau蛋白磷酸化和Aβ代谢的影响及机制；研究AGEs对大鼠空间记忆能力的影响以及早期干预拟AD模型的AGEs生成能否预防脑结构和功能的损伤。
[方法]
体外研究：我们采用合成的AGEs处理SK-N-SH细胞和原代海马神经元,并用高级糖化终产物受体(receptor for advanced glycation endproducts, RAGE)抗体、糖原合酶激酶-3(glycogen synthase kinase-3, GSK-3)抑制剂(SB216763, LiCl)、细胞外信号调节激酶1和2(Extracellular Signal Regulated Kinase 1/2, Erk1/2)抑制剂(PD98059)或p38抑制剂(SB202190)与AGEs共处理。
体内研究：我们采用立体定位注射的方法对SD大鼠双侧海马注射AGEs,合并注射RAGE抗体或GSK-3抑制剂。为研究早期干预AGEs对AD的影响,我们选用6月龄拟AD模型Tg2576小鼠,连续3个月皮下注射氨基胍(aminoguanidine, AG)或生理盐水(normal saline, NS)。
采用免疫印迹或免疫组织化学检测tau蛋白磷酸化、蛋白激酶或磷酸酯酶的活性依赖性修饰以及突触蛋白的表达水平；采用酶联免疫吸附法ELISA检测Ap的水平；采用免疫共沉淀检测Ap的的糖化水平；采用长时程电位增强(long term potentiation, LTP)技术检测突触可塑性；采用转染绿色荧光蛋白检测原代海马神经元树突棘的数目和形态；采用水迷宫试验检测大鼠的空间记忆功能。
[结果]
1) AGEs可通过RAGE/GSK-3通路诱导tau蛋白过度磷酸化。
AGEs可诱导SK-N-SH细胞、原代海马神经元和SD大鼠的tau蛋白过度磷酸化。为了探讨AGEs诱导tau蛋白过度磷酸化的机制,我们用AGEs(最佳浓度50μg/ml,最佳时间24h)处理SK-N-SH细胞,发现AGEs在诱导tau蛋白过度磷酸化的同时,伴随有RAGE mRNA和蛋白水平的升高、Akt活性的抑制以及蛋白激酶(GSK-3、Erk1/2和p38)活性的激活,而其它蛋白激酶,如c-Jun氨基末端激酶(c-Jun N-terminal kinase, JNK),钙调蛋白激酶Ⅱ(calcium calmodulin-dependent protein kinaseⅡ, CaMKⅡ),蛋白激酶A调节亚基(regulary unit of protein kinase A Iα, PKA RIα)和PKA RⅡβ,以及磷酸酯酶2A (protein phosphatases 2A, PP2A)的活性无明显变化。为了进一步确定以上有活性改变的蛋白分子在AGEs诱导的tau蛋白过度磷酸化中的作用,我们采用RAGE抗体和相关蛋白激酶抑制剂与AGEs共处理,结果发现当共处理RAGE抗体或GSK-3抑制剂时可有效逆转AGEs诱导的tau蛋白过度磷酸化,而同时抑制Erk1/2或p38无明显变化,提示RAGE和GSK-3可能在AGEs诱导的tau蛋白过度磷酸化中起重要作用。
2) AGEs损伤大鼠空间记忆能力,其机制涉及AGEs通过RAGE/GSK-3通路导致tau蛋白过度磷酸化、LTP抑制、突触蛋白下降、树突棘减少。
我们发现,注射AGEs损伤SD大鼠空间记忆能力。为了探讨相关机制,我们检测了与空间记忆相关的指标,如tau蛋白磷酸化、LTP和突触相关蛋白。发现注射AGEs可导致tau蛋白过度磷酸化、LTP抑制、多种突触蛋白(尤其是突触后蛋白PSD95、PSD93、NR2A和NR2B)水平降低。同时,伴随有RAGE水平升高、AKt抑制和GSK-3激活。为进一步研究RAGE和GSK-3的作用,我们采用了RAGE抗体或GSK-3抑制剂与AGEs一起海马定位注射,结果发现同时阻断RAGE或抑制GSK-3可显著改善AGEs诱导的大鼠空间记忆障碍,伴随tau蛋白磷酸化、LTP和突触蛋白水平的恢复。
3)早期阻止AGEs聚积可有效预防拟AD模型空间学习记忆损伤,伴随Aβ和tau蛋白磷酸化水平降低、突触蛋白含量恢复。
我们选择从6月龄小鼠开始皮下注射氨基胍AG。对照组注射同体积生理盐水NS。3个月后,发现给予AG可明显抑制AGEs的生成；同时,AG干预组小鼠的空间学习记忆能力改善、tau蛋白在Thr231和Ser396位点磷酸化水平降低、突触蛋白和相关记忆分子水平升高、Aβ水平明显降低。用免疫共沉淀方法检测AGEs与Aβ的相互作用,发现Ap可明显被AGE化。
[结论]
1) AGEs可通过RAGE/GSK-3信号通路诱导tau蛋白过度磷酸化。
2)Aβ在体内可发生糖化,糖化能促进Aβ的聚积。
3) AGEs可通过RAGE/GSK-3信号通路诱导大鼠空间记忆能力的损伤,早期抑制AGEs生成可逆转拟AD模型Tg2576小鼠的空间学习记忆的损伤。
Background The hallmark lesions observed in Alzheimer disease (AD) brain is the formation of numerous neurofibrillary tangles (NFTs) and senile plaques (SPs), which are respectively composed of the hyperphosphorylated tau and (3-amyloid (Aβ). The advanced glycation endproducts (AGEs) are produced from a complex nonenzymatic multistep reaction of reducing sugars or dicarboneyl compounds, such as glyoxal and methylglyoxal, with the amino groups of proteins, especially the N-terminal amino groups and side chains of lysine and arginine. AGEs are elevated in the AD brains and the AGEs can stimulateβ-amyloid production and colocalize with NFTs and SPs, suggesting that AGEs play an important role in pathogenesis of AD. However, whether and how AGEs may cause AD-like tau hyperphosphorylation, whether elevated AGEs could induce spatial memory impairment, and whether early decreasing AGEs could reverse spatial memory defict of AD model are not reported.
Objective It was to investigate the effects of AGEs on tau phosphorlation, Aβmetabolism and spatial memory, and whether decreasing AGEs accumulation could prevent memory deficits and AD-like pathologies in Tg2576 mice.
Methods In vitro, we used exogenous AGEs to treat SK-N-SH cells and primary hippocampal neurons. RAGE antibody or inhibitors of GSK-3 (SB216763, LiC1), Erk1/2 (PD98059) and p38 (SB202190) were simultaneously co-incubated with AGEs. In vivo, we injected AGEs with or without RAGE antibody or LiCl into the hippocampus of SD rats. In order to study early inhibition of AGEs on AD model,6-m Tg2576 mice were used and subcutaneously injected with 0.9% normal saline (NS) or aminoguanidine (AG) for 3 m. Tau phosphorylation, protein kinases and phosphoesterase, synapse proteins were measured with western blotting or immunohischemistry. The level of A(3 and AGEs were measured with ELISA or dot blot. The interaction of Aβand AGEs was investigated with co-immunoprecipitation. Synapse plasticity was examined with long term potentiation (LTP). Spatial memory was investigated with Morris water maze.
Results
(1) AGEs could induce tau hyperphosphorylation through RAGE/GSK-3 pathway.
First, we found AGEs induced tau hyperphosphorylation in SK-N-SH cells, primary hippocampal neurons and SD rats. Then, to study the underlying mechanism, we used the optimal concentration of AGEs (50μg/ml) to treat SK-N-SH cells for the optimal time (24 h). We observed that, with AGEs-induced tau hyperphosphorylation, mRNA and protein level of RAGE (receptor for AGEs) were elevated, the activity of akt was inhibited, and GSK-3, p38 and Erk1/2 were activated. At the last, to further indentify the role of the above chanded proteins in AGEs-induced tau hyperphosphorylation, we used Co-incubation of RAGE antibody or GSK-3 inhibitor with AGE to treat cells. We found that only RAGE antibody and GSK-3 inhibitor could insignificantly reverse tau hyperphosphorylation induced by AGEs, suggesting AGEs could induce tau hyperphosphorylation through RAGE/GSK-3 pathway.
(2) AGEs could induce spatial memory deficit of SD rats, with tau hyperphosphorylation, inhibition of LTP, decline of synapse-related proteins through RAGE/GSK-3 pathway.
First, we found that AGEs induced spatial memory deficit of SD rats. Then, to explore the possible mechanism, we investigated memory-related markers. We found that, with the impairment of memory, tau was hyperphosphorylated, LTP was inhibited, and synaptic proteins, especially postsynaptic proteins, were decreased. Meanwhile, with the hyperphosphorylated tau, RAGE was elevated, akt was inhibited, and GSK-3 was activated. And then, to further study the underlying mechanism of memory deficit, rats were co-injected with AGEs plus RAGE antibody or GSK-3 inhibitor, and found that co-injection not only significantly improve tau hyperphosphorylation, inhibiton of LTP, and decrease of synaptic proteins, but also reverse AGEs-induced memory impairment.
(3) Early inhibiton of AGEs could revesrse memory deficit of AD model, which may be mediated by AGEs-induced decrease of A(3 production.
We selected 6-m mice to treate AG. Then,6-m Tg2576 mice were used and subcutaneously injected with normal saline (NS) or aminoguanidine (AG) for 3 m. We found that AG treatment could effectively inhibit the production of AGEs, and compared with age-matched groups injected with NS, decrease of AGEs significantly reverse memory deficit of Tg2576 mice, with decrese of tau hyperphosphorylation at site of Thr231 and Ser396, and increase of synaptic proteins. Meanwhile, after treatment of AG, production of Aβwas declined with the decreae of AGEs. To explore the possible mechanism of decrease of Aβ, we used co-immunoprecipitation to study the interaction of AGEs and Aβ, and found that Aβcould be glycated by AGEs.
Conclusion Our data reveal that AGEs can induce tau hyperphosphorylation and Aβoverproduction; AGEs cause impairments of spatial memory through RAGE-mediated GSK-3 activation; Early inhibiton of AGEs could reverse memory deficit in Tg2576 mice.
引文
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7 Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proceedings of the National Academy of Sciences of the United States of America. 1986;83(13):4913-4917.
8 Bigl K, Gaunitz F, Schmitt A, Rothemund S, Schliebs R, Munch G, Arendt T. Cytotoxicity of advanced glycation endproducts in human micro- and astroglial cell lines depends on the degree of protein glycation. Journal of Neural Transmission.2008;115(11):1545-1556.
9 Price CL, Sharp PS, North ME, Rainbow SJ, Knight SC. Advanced glycation end products modulate the maturation and function of peripheral blood dendritic cells. Diabetes.2004;53(6):1452-1458.
10 Brandeis R, Brandys Y, Yehuda S. The use of the Morris Water Maze in the study of memory and learning. International Journal of Neuroscience.1989;48(1-2):29-69.
11 Sato T, Shimogaito N, Wu X, Kikuchi S, Yamagishi S, Takeuchi M. Toxic advanced glycation end products (TAGE) theory in Alzheimer's disease. American Journal of Alzheimer's Disease and Other Dementias.2006;21(3):197-208.
12 Cochrane SM, Furth AJ. The role of bound lipid and transition metal in the formation of fluorescent advanced glycation endproducts by human serum albumin. Biochemical Society Transactions. 1993;21(2):97S.
13 Loske C, Neumann A, Cunningham AM, Nichol K, Schinzel R, Riederer P, Munch G Cytotoxicity of advanced glycation endproducts is mediated by oxidative stress. Journal of Neural Transmission. 1998;105(8-9):1005-1015.
14 Sekido H, Suzuki T, Jomori T, Takeuchi M, Yabe-Nishimura C, Yagihashi S. Reduced cell replication and induction of apoptosis by advanced glycation end products in rat Schwann cells. Biochemical and Biophysical Research Communications.2004;320(1):241-248.
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19 Makita Z, Bucala R, Rayfield EJ, Friedman EA, Kaufman AM, Korbet SM, Barth RH, Winston JA, Fuh H, Manogue KR, et al. Reactive glycosylation endproducts in diabetic uraemia and treatment of renal failure. Lancet.1994;343(8912):1519-1522.
20 Makita Z, Radoff S, Rayfield EJ, Yang Z, Skolnik E, Delaney V, Friedman EA, Cerami A, Vlassara H. Advanced glycosylation end products in patients with diabetic nephropathy. The New England Journal of Medicine.1991;325(12):836-842.
21 Vlassara H, Striker LJ, Teichberg S, Fuh H, Li YM, Steffes M. Advanced glycation end products induce glomerular sclerosis and albuminuria in normal rats. Proceedings of the National Academy of Sciences of the United States of America.1994;91(24):11704-11708.
22 Yoon YW, Kang TS, Lee BK, Chang W, Hwang KC, Rhee JH, Min PK, Hong BK, Rim SJ, Kwon HM. Pathobiological role of advanced glycation endproducts via mitogen-activated protein kinase dependent pathway in the diabetic vasculopathy. Experimental & Molecular Medicine. 2008;40(4):398-406.
23 Genuth S, Sun W, Cleary P, Sell DR, Dahms W, Malone J, Sivitz W, Monnier VM. Glycation and carboxymethyllysine levels in skin collagen predict the risk of future 10-year progression of diabetic retinopathy and nephropathy in the diabetes control and complications trial and epidemiology of diabetes interventions and complications participants with type 1 diabetes. Diabetes. 2005;54(11):3103-3111.
24 Ke YD, Delerue F, Gladbach A, Gotz J, Ittner LM. Experimental diabetes mellitus exacerbates tau pathology in a transgenic mouse model of Alzheimer's disease. Plos One.2009;4(11):e7917.
25 Takeda S, Sato N, Uchio-Yamada K, Sawada K, Kunieda T, Takeuchi D, Kurinami H, Shinohara M, Rakugi H, Morishita R. Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Abeta deposition in an Alzheimer mouse model with diabetes. Proceedings of the National Academy of Sciences of the United States of America.2010;107(15):7036-7041.
26 Maher PA, Schubert DR. Metabolic links between diabetes and Alzheimer's disease. Expert Review of Neurotherapeutics.2009;9(5):617-630.
27 Valente T, Gella A, Fernandez-Busquets X, Unzeta M, Durany N. Immunohistochemical analysis of human brain suggests pathological synergism of Alzheimer's disease and diabetes mellitus. Neurobiology of Disease.2010;37(1):67-76.
28 Xu W, Qiu C, Winblad B, Fratiglioni L. The effect of borderline diabetes on the risk of dementia and Alzheimer's disease. Diabetes.2007;56(1):211-216.
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31 Neeper M, Schmidt AM, Brett J, Yan SD, Wang F, Pan YC, Elliston K, Stern D, Shaw A. Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. The Journal of Biological Chemistry.1992;267(21):14998-15004.
32 Brett J, Schmidt AM, Yan SD, Zou YS, Weidman E, Pinsky D, Nowygrod R, Neeper M, Przysiecki C, Shaw A, et al. Survey of the distribution of a newly characterized receptor for advanced glycation end products in tissues. The American Journal of Pathology.1993;143(6):1699-1712.
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34 Casselmann C, Reimann A, Friedrich I, Schubert A, Silber RE, Simm A. Age-dependent expression of advanced glycation end product receptor genes in the human heart. Gerontology.2004;50(3):127-134.
35 Hudson BI, Carter AM, Harja E, Kalea AZ, Arriero M, Yang H, Grant PJ, Schmidt AM. Identification, classification, and expression of RAGE gene splice variants. The FASEB Journal. 2008;22(5):1572-1580.
36 Sasaki N, Fukatsu R, Tsuzuki K, Hayashi Y, Yoshida T, Fujii N, Koike T, Wakayama I, Yanagihara R, Garruto R, Amano N, Makita Z. Advanced glycation end products in Alzheimer's disease and other neurodegenerative diseases. The American Journal of Pathology.1998;153(4):1149-1155.
37 Yesavage JA, O'Hara R, Kraemer H, Noda A, Taylor JL, Ferris S, Gely-Nargeot MC, Rosen A, Friedman L, Sheikh J, Derouesne C. Modeling the prevalence and incidence of Alzheimer's disease and mild cognitive impairment. Journal of Psychiatric Research.2002;36(5):281-286.
38 Schmidt AM, Yan SD, Yan SF, Stern DM. The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses. The Journal of Clinical Investigation. 2001;108(7):949-955.
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42 Guglielmotto M, Aragno M, Tamagno E, Vercellinatto I, Visentin S, Medana C, Catalano MG, Smith MA, Perry G, Danni O, Boccuzzi G, Tabaton M. AGEs/RAGE complex upregulates BACE1 via NF-kappa B pathway activation. Neurobiology of Aging.2010. [Epub ahead of print]
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60 Yan SD, Chen X, Schmidt AM, Brett J, Godman G, Zou YS, Scott CW, Caputo C, Frappier T, Smith MA, et al. Glycated tau protein in Alzheimer disease:a mechanism for induction of oxidant stress. Proceedings of the National Academy of Sciences of the United States of America. 1994;91(16):7787-7791.
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2 Lobo A, Launer LJ, Fratiglioni L, Andersen K, Di Carlo A, Breteler MM, Copeland JR, Dartigues JF, Jagger C, Martinez-Lage J, Soininen H, Hofman A. Prevalence of dementia and major subtypes in Europe:A collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology.2000;54(11 Suppl 5):S4-9.
3 Wang JZ, Liu F. Microtubule-associated protein tau in development, degeneration and protection of neurons. Progress in Neurobiology.2008;85(2):148-175.
4 Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, Wisniewski HM. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. The Journal of Biological Chemistry.1986;261(13):6084-6089.
5 Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proceedings of the National Academy of Sciences of the United States of America. 1986;83(13):4913-4917.
6 Glenner GG, Wong CW. Alzheimer's disease and Down's syndrome:sharing of a unique cerebrovascular amyloid fibril protein. Biochemical and Biophysical Research Communications.1984;122(3):1131-1135.
7 Bigl K, Gaunitz F, Schmitt A, Rothemund S, Schliebs R, Munch G, Arendt T. Cytotoxicity of advanced glycation endproducts in human micro- and astroglial cell lines depends on the degree of protein glycation. Journal of Neural Transmission.2008;115(11):1545-1556.
8 Price CL, Sharp PS, North ME, Rainbow SJ, Knight SC. Advanced glycation end products modulate the maturation and function of peripheral blood dendritic cells. Diabetes. 2004;53(6):1452-1458.
9 Brandeis R, Brandys Y, Yehuda S. The use of the Morris Water Maze in the study of memory and learning. International Journal of Neuroscience.1989;48(1-2):29-69.
10 Sato T, Shimogaito N, Wu X, Kikuchi S, Yamagishi S, Takeuchi M. Toxic advanced glycation end products (TAGE) theory in Alzheimer's disease. American Journal of Alzheimer's Disease and Other Dementias.2006;21(3):197-208.
11 Cochrane SM, Furth AJ. The role of bound lipid and transition metal in the formation of fluorescent advanced glycation endproducts by human serum albumin. Biochemical Society Transactions.1993;21(2):97S.
12 Loske C, Neumann A, Cunningham AM, Nichol K, Schinzel R, Riederer P, Munch G. Cytotoxicity of advanced glycation endproducts is mediated by oxidative stress. Journal of Neural Transmission.1998;105(8-9):1005-1015.
13 Makita Z, Bucala R, Rayfield EJ, Friedman EA, Kaufman AM, Korbet SM, Barth RH, Winston JA, Fuh H, Manogue KR, et al. Reactive glycosylation endproducts in diabetic uraemia and treatment of renal failure. Lancet.1994;343(8912):1519-1522.
14 Makita Z, Radoff S, Rayfield EJ, Yang Z, Skolnik E, Delaney V, Friedman EA, Cerami A, Vlassara H. Advanced glycosylation end products in patients with diabetic nephropathy. The New England Journal of Medicine.1991;325(12):836-842.
15 Vlassara H, Striker LJ, Teichberg S, Fuh H, Li YM, Steffes M. Advanced glycation end products induce glomerular sclerosis and albuminuria in normal rats. Proceedings of the National Academy of Sciences of the United States of America.1994;91(24):11704-11708.
16 Yoon YW, Kang TS, Lee BK, Chang W, Hwang KC, Rhee JH, Min PK, Hong BK, Rim SJ, Kwon HM. Pathobiological role of advanced glycation endproducts via mitogen-activated protein kinase dependent pathway in the diabetic vasculopathy. Experimental & Molecular Medicine.2008;40(4):398-406.
17 Genuth S, Sun W, Cleary P, Sell DR, Dahms W, Malone J, Sivitz W, Monnier VM. Glycation and carboxymethyllysine levels in skin collagen predict the risk of future 10-year progression of diabetic retinopathy and nephropathy in the diabetes control and complications trial and epidemiology of diabetes interventions and complications participants with type 1 diabetes. Diabetes.2005;54(11):3103-3111.
18 Ke YD, Delerue F, Gladbach A, Gotz J, Ittner LM. Experimental diabetes mellitus exacerbates tau pathology in a transgenic mouse model of Alzheimer's disease. Plos One. 2009;4(11):e7917.
19 Takeda S, Sato N, Uchio-Yamada K, Sawada K, Kunieda T, Takeuchi D, Kurinami H, Shinohara M, Rakugi H, Morishita R. Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Abeta deposition in an Alzheimer mouse model with diabetes. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(15):7036-7041.
20 Maher PA, Schubert DR. Metabolic links between diabetes and Alzheimer's disease. Expert Review of Neurotherapeutics.2009;9(5):617-630.
21 Valente T, Gella A, Fernandez-Busquets X, Unzeta M, Durany N. Immunohistochemical analysis of human brain suggests pathological synergism of Alzheimer's disease and diabetes mellitus. Neurobiology of Disease.2010;37(1):67-76.
22 Xu W, Qiu C, Winblad B, Fratiglioni L. The effect of borderline diabetes on the risk of dementia and Alzheimer's disease. Diabetes.2007;56(1):211-216.
23 Wang SH, Sun ZL, Guo YJ, Yuan Y, Li L. PPARgamma-mediated advanced glycation end products regulation of neural stem cells. Molecular and Cellular Endocrinology. 2009;307(1-2):176-184.
24 Duran-Jimenez B, Dobler D, Moffatt S, Rabbani N, Streuli CH, Thornalley PJ, Tomlinson DR, Gardiner NJ. Advanced glycation end products in extracellular matrix proteins contribute to the failure of sensory nerve regeneration in diabetes. Diabetes. 2009;58(12):2893-2903.
25 Shuvaev VV, Laffont I, Serot JM, Fujii J, Taniguchi N, Siest G. Increased protein glycation in cerebrospinal fluid of Alzheimer's disease. Neurobiology of Aging.2001;22(3):397-402.
26 Bar KJ, Franke S, Wenda B, Muller S, Kientsch-Engel R, Stein G, Sauer H. Pentosidine and N(epsilon)-(carboxymethyl)-lysine in Alzheimer's disease and vascular dementia. Neurobiology of Aging.2003;24(2):333-338.
27 Sasaki N, Toki S, Chowei H, Saito T, Nakano N, Hayashi Y, Takeuchi M, Makita Z. Immunohistochemical distribution of the receptor for advanced glycation end products in neurons and astrocytes in Alzheimer's disease. Brain Research.2001;888(2):256-262.
28 Richter T, Munch G, Luth HJ, Arendt T, Kientsch-Engel R, Stahl P, Fengler D, Kuhla B. Immunochemical crossreactivity of antibodies specific for "advanced glycation endproducts" with "advanced lipoxidation endproducts". Neurobiology of Aging.2005;26(4):465-474.
29 Ko LW, Ko EC, Nacharaju P, Liu WK, Chang E, Kenessey A, Yen SH. An immunochemical study on tau glycation in paired helical filaments. Brain Research.1999;830(2):301-313.
30 Yan SD, Yan SF, Chen X, Fu J, Chen M, Kuppusamy P, Smith MA, Perry G, Godman GC, Nawroth P, et al. Non-enzymatically glycated tau in Alzheimer's disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid beta-peptide. Nature Medicine.1995;1(7):693-699.
31 Yan SD, Chen X, Schmidt AM, Brett J, Godman G, Zou YS, Scott CW, Caputo C, Frappier T, Smith MA, et al. Glycated tau protein in Alzheimer disease:a mechanism for induction of oxidant stress. Proceedings of the National Academy of Sciences of the United States of America.1994;91(16):7787-7791.
32 Krautwald M, Munch G. Advanced glycation end products as biomarkers and gerontotoxins-A basis to explore methylglyoxal-lowering agents for Alzheimer's disease? Experimental Gerontology.2010;45(10):744-751.
33 Sasaki N, Fukatsu R, Tsuzuki K, Hayashi Y, Yoshida T, Fujii N, Koike T, Wakayama I, Yanagihara R, Garruto R, Amano N, Makita Z. Advanced glycation end products in Alzheimer's disease and other neurodegenerative diseases. The American Journal of Pathology.1998;153(4):1149-1155.
34 Staniszewska M, Leszek J, Malyszczak K, Gamian A. Are advanced glycation end-products specific biomarkers for Alzheimer's disease? International Journal of Geriatric Psychiatry. 2005;20(9):896-897.
35 Loy CT, Twigg SM. Growth factors, AGEing, and the diabetes link in Alzheimer's disease. Journal ofAlzheimers Disease.2009;16(4):823-831.
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37 Vitek MP, Bhattacharya K, Glendening JM, Stopa E, Vlassara H, Bucala R, Manogue K, Cerami A. Advanced glycation end products contribute to amyloidosis in Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America. 1994;91(11):4766-4770.
38 Loske C, Gerdemann A, Schepl W, Wycislo M, Schinzel R, Palm D, Riederer P, Munch G. Transition metal-mediated glycoxidation accelerates cross-linking of beta-amyloid peptide. European Journal of Biochemistry.2000;267(13):4171-4178.
39 Srikanth V, Maczurek A, Phan T, Steele M, Westcott B, Juskiw D, Munch G. Advanced glycation endproducts and their receptor RAGE in Alzheimer's disease. Neurobiology of Aging.2009;32(5):763-777.
40 Neeper M, Schmidt AM, Brett J, Yan SD, Wang F, Pan YC, Elliston K, Stern D, Shaw A. Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. The Journal of Biological Chemistry.1992;267(21):14998-15004.
41 Brett J, Schmidt AM, Yan SD, Zou YS, Weidman E, Pinsky D, Nowygrod R, Neeper M, Przysiecki C, Shaw A, et al. Survey of the distribution of a newly characterized receptor for advanced glycation end products in tissues. The American Journal of Pathology. 1993;143(6):1699-1712.
42 Casselmann C, Reimann A, Friedrich I, Schubert A, Silber RE, Simm A. Age-dependent expression of advanced glycation end product receptor genes in the human heart. Gerontology.2004;50(3):127-134.
43 Hudson BI, Carter AM, Harja E, Kalea AZ, Arriero M, Yang H, Grant PJ, Schmidt AM. Identification, classification, and expression of RAGE gene splice variants. The Faseb Journal.2008;22(5):1572-1580.
44 Yesavage JA, O'Hara R, Kraemer H, Noda A, Taylor JL, Ferris S, Gely-Nargeot MC, Rosen A, Friedman L, Sheikh J, Derouesne C. Modeling the prevalence and incidence of Alzheimer's disease and mild cognitive impairment. Journal of Psychiatric Research. 2002;36(5):281-286.
45 Schmidt AM, Yan SD, Yan SF, Stern DM. The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses. The Journal of Clinical Investigation. 2001;108(7):949-955.
46 Guglielmotto M, Aragno M, Tamagno E, Vercellinatto I, Visentin S, Medana C, Catalano MG, Smith MA, Perry G, Danni O, Boccuzzi G, Tabaton M. AGEs/RAGE complex upregulates BACE1 via NF-kappaB pathway activation. Neurobiology of Aging.[Epub ahead of print].
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