辅酶Q10对携带突变的PS-1的老年转基因鼠β-淀粉样肽和tau蛋白磷酸化的影响及机制的探讨
|
摘要
阿尔茨海默病(Alzheimer’s disease, AD)以β-淀粉样肽(β-amyloid,Aβ)大量生成和tau蛋白过度磷酸化为主要特征。Aβ与异常磷酸化的tau蛋白的联系及其分子机制尚不清楚,仍然没有有效的措施能阻止AD的发展。在目前研究中,我们发现患有家族性阿尔茨海默病早老素1-L235P(在密码子235位亮氨酸变成脯氨酸)突变的老年(16～17月龄)转基因鼠Aβ42的生成和在细胞内的沉积显著增多。同时,我们检测了tau蛋白的磷酸化修饰,发现老年转基因鼠丝氨酸396,404和198/199/202位点tau磷酸化程度比同月龄正常鼠显著升高。我们也观察到老年转基因鼠丙二醛(malondialdehyde,MDA)水平比同月龄正常鼠升高,而超氧化物歧化酶(superoxide dismutase,SOD)水平则降低,表明转基因鼠氧化应激水平增高。我们进一步检测了Akt-GSK-3β信号途径的修饰,发现老年转基因鼠Akt、GSK-3β的磷酸化程度降低,提示Akt-GSK-3β信号途径发生抑制。外源性给予辅酶Q10(一个强有力的抗氧化剂和自由基清除剂),不仅能部分降低MDA的水平,增加SOD的活性,而且能减少Aβ42的生成,降低tau蛋白过度磷酸化,同时伴有Akt-GSK-3β信号途径的恢复。这些结果表明早老素-1突变选择性地增加Aβ42的生成和在细胞内的沉积,并使tau蛋白过度磷酸化。后者可能是细胞内过多的Aβ诱导的氧化应激的下游事件,其机制可能涉及氧化应激诱导的Akt-GSK-3β信号途径的抑制。辅酶Q10通过抗氧化特性发挥其神经保护作用。这些结果也提示早老素-1突变的致病角色是淀粉样肽级联反应和tau病理的上游事件,而辅酶Q10可能是一个潜在有用的治疗阿尔茨海默病的药物。
小结
我们的研究发现:1)在携带L235P突变的早老素-1的老年转基因鼠的海马和皮层发生了AD样病理改变:β淀粉样变和tau蛋白过度磷酸化。2)该老年转基因鼠的相应脑区表现出了增强的氧化应激反应和Akt-GSK-3β信号途径的抑制。3)外源性补充辅酶Q10不仅降低了氧化应激反应水平,而且能减少Aβ42的生成,降低tau蛋白的过度磷酸化,同时伴有Akt-GSK-3β信号途径的恢复。这些结果表明突变的早老素-1是淀粉样肽级联反应和tau蛋白病理改变的上游事件,氧化应激可能在介导突变的早老素-1的致病作用中发挥重要作用,而辅酶Q10可能是一个潜在有用的治疗阿尔茨海默病的药物。
第二部分
褪黑素改善花萼海绵诱癌素诱导的轴突运输障碍和大鼠空间记忆损伤
最近,我们发现褪黑素能保护SH-SY5Y成神经瘤细胞免于花萼海绵诱癌素(calyculin A,CA)引起的神经细丝损伤和神经毒性作用。在我们现在的研究中,通过双侧海马注射CA—一个有效的特异性蛋白磷酸酯酶2A(protein phosphatase -2A,PP-2A)和蛋白磷酸酯酶1(protein phosphatase-1,PP-1)的抑制剂,建立大鼠空间记忆损伤模型,在整体上研究了褪黑素对大鼠空间记忆的保护作用。结果表明在CA注射前9天腹腔内给予褪黑素,不仅显著改善了CA引起的记忆损伤,而且对CA诱导的神经细胞骨架蛋白tau和神经细丝的过度磷酸化也有保护作用。为进一步揭示褪黑素上述保护作用的潜在机制,用pEGFP标记N2a细胞内中分子量神经细丝,通过全内反射显微成像系统研究轴突运输,我们在轴突样突起中发现褪黑素能部分地逆转CA诱导的轴突运输障碍。免疫印迹结果显示褪黑素还能抑制CA诱导的骨架蛋白tau和神经细丝的过度磷酸化。此外,我们建立了轴突样突起生长的细胞模型,用以揭示褪黑素对磷酸酯酶活性处于抑制状态时细胞形态学改变的影响,并借助体视学系统分析细胞突起的长度变化。我们发现CA处理抑制细胞突起的生长,长时间使用CA处理引起细胞突起缩短,并可见早期神经退行性轴突曲张样改变,褪黑素明显阻止这些病理改变。这些结果表明褪黑素不仅能改善因PP-2A和PP-1活性抑制所致的轴突转运障碍,也能抑制神经细胞退行性变性,这些效应可能构成了褪黑素对磷酸酯酶活性抑制所引起的记忆缺失的保护作用的基础。
小结
我们的研究发现:褪黑素不仅部分改善了花萼海绵诱癌素诱导的神经细丝的运输障碍及细胞退化样的改变,降低了骨架蛋白tau和神经细丝的过度磷酸化,而且改善了花萼海绵诱癌素诱导的空间记忆保留障碍。这些结果提示骨架蛋白的过度磷酸化可能在介导轴突运输障碍,轴突病变及空间记忆损伤等AD病理改变中起关键作用,褪黑素通过降低骨架蛋白的过度磷酸化部分逆转上述病理改变,提示褪黑素可能是有效治疗AD的药物。
Alzheimer's disease is characterized byβ-amyloid (Aβ) overproduction and tau hyperphosphorylation. The underlying mechanisms linking Aβand aberrant tau phosphorylation are poorly understood, and therefore there are no effective therapeutic measures for arresting the AD pathology. In our present study, we found that familial Alzheimer disease mutation with presenilin 1-L235P(leucine-to-proline mutation at codon 235 ) transgenic mice (PS-1 Tg) enhanced the generation of Aβ42, and significantly increased intracellular Aβ42 deposition in the brain of the aged Tg mice (16-17 months old). We also determined the alterations of phosphorylated tau and found that phosphorylation of tau at pSer396, Tau-1 (Ser198/199/202) and pSer404 epitopes was significantly increased in the aged Tg mice compared with the age-matched wild type mice (WT). Meanwhile, we detected an increased oxidative stress reaction as evidenced by elevated level of malondialdehyde (MDA) and decreased activity of superoxide dismutase (SOD) in the aged Tg mice, compared to the WT mice. We further detected the alterations in Akt-GSK-3βsignaling pathway and found a decreased phosphorylation of Akt, glycogen synthase kinase (GSK)-3βin the aged Tg mice. Exogenous supplementation of coenzyme Q10 (CoQ10), a powerful antioxidant and free radical scavenger, not only partially decreased MDA level and up-regulated the activity of SOD, but also arrested Aβ42 level and tau hyperphosphorylation, concurrently accompanied with a restoration of Akt-GSK-3βsignaling. These results suggest that the mutated PS-1 increases Aβ42 production and intracellular deposition selectively and tau hyperphosphorylation. The latter may be a consequence of intracellular overproduced Aβinduced-oxidative stress and the mechanisms may involve depression of oxidative stress-induced Akt-GSK-3βsignaling events. The neuroprotective effects of CoQ10 may act through its antioxidant property. Our data also indicate that the pathogenic role of the mutated PS-1 is upstream of the amyloid cascade and taupathy, and CoQ10 might be potentially useful for therapy of Alzheimer’s disease.
Part two
Melatonin Meliorates Calyculin A-induced Axonal Transport Defects and Spatial Memory Retention Impairment in Rats
We have recently found that melatonin protects SH-SY5Y neuroblastoma cells from calyculin A(CA)-induced neurofilament impairment and neurotoxicity. In the present study, we further investigated the in vivo effect of melatonin on spatial memory retention in rats by bilateral injection of CA, a potent and specific inhibitor of protein phosphatase-2A (PP-2A) and protein phosphatase-1 (PP-1) into hippocampus. We found that the supplementation of melatonin by intraperitoneal injection for 9 days before injecting CA not only significantly improves CA-induced memory retention deficits of the rats in the Morris Water-Maze Test, but also decreases hyperphosphorylation of neuronal cytoskeletal protein tau and neurofilaments. To further explore the underlying mechanisms of the protective effect of melatonin on spatial memory deficit in rats induced by CA, we analyzed the axonal transport by a time-lapse recording of pEGFP-labeled neurofilament-M (pEGFP-NF-M) subunit in live neuroblastoma N2a cells and found that melatonin partially reversed CA-induced impairment of transport of pEGFP- NF-M in the axon-like processes of the cells. In the meantime, we found by western blot that melatonin also decreased CA-induced hyperphosphorylation of cytoskeletal proteins. In addition, we explored the effect of melatonin on the morphological alteration of the cells during inhibition of the phosphatases by establishing a cell model showing steady outgrowth of axon-like cell processes and employed a stereological system to analyze the retraction of the processes. We found CA-treatment inhibited outgrowth of the cell processes and prolonged treatment with CA caused retraction of the processes and meanwhile, the early neurodegenerative varicosities were also obvious in the CA-treated cells, and the administration of melatonin significantly arrested these pathological alterations. These data suggest that melatonin not only meliorated impaired intracellular transport induced by suppression of PP-2A and PP-1, but also cell degeneration, which may underlie the basis of the effects of protection of melatonin on memory deficits induced by suppression of the phosphatases.
小结
我们的研究发现:1)在携带L235P突变的早老素-1的老年转基因鼠的海马和皮层发生了AD样病理改变:β淀粉样变和tau蛋白过度磷酸化。2)该老年转基因鼠的相应脑区表现出了增强的氧化应激反应和Akt-GSK-3β信号途径的抑制。3)外源性补充辅酶Q10不仅降低了氧化应激反应水平,而且能减少Aβ42的生成,降低tau蛋白的过度磷酸化,同时伴有Akt-GSK-3β信号途径的恢复。这些结果表明突变的早老素-1是淀粉样肽级联反应和tau蛋白病理改变的上游事件,氧化应激可能在介导突变的早老素-1的致病作用中发挥重要作用,而辅酶Q10可能是一个潜在有用的治疗阿尔茨海默病的药物。
第二部分
褪黑素改善花萼海绵诱癌素诱导的轴突运输障碍和大鼠空间记忆损伤
最近,我们发现褪黑素能保护SH-SY5Y成神经瘤细胞免于花萼海绵诱癌素(calyculin A,CA)引起的神经细丝损伤和神经毒性作用。在我们现在的研究中,通过双侧海马注射CA—一个有效的特异性蛋白磷酸酯酶2A(protein phosphatase -2A,PP-2A)和蛋白磷酸酯酶1(protein phosphatase-1,PP-1)的抑制剂,建立大鼠空间记忆损伤模型,在整体上研究了褪黑素对大鼠空间记忆的保护作用。结果表明在CA注射前9天腹腔内给予褪黑素,不仅显著改善了CA引起的记忆损伤,而且对CA诱导的神经细胞骨架蛋白tau和神经细丝的过度磷酸化也有保护作用。为进一步揭示褪黑素上述保护作用的潜在机制,用pEGFP标记N2a细胞内中分子量神经细丝,通过全内反射显微成像系统研究轴突运输,我们在轴突样突起中发现褪黑素能部分地逆转CA诱导的轴突运输障碍。免疫印迹结果显示褪黑素还能抑制CA诱导的骨架蛋白tau和神经细丝的过度磷酸化。此外,我们建立了轴突样突起生长的细胞模型,用以揭示褪黑素对磷酸酯酶活性处于抑制状态时细胞形态学改变的影响,并借助体视学系统分析细胞突起的长度变化。我们发现CA处理抑制细胞突起的生长,长时间使用CA处理引起细胞突起缩短,并可见早期神经退行性轴突曲张样改变,褪黑素明显阻止这些病理改变。这些结果表明褪黑素不仅能改善因PP-2A和PP-1活性抑制所致的轴突转运障碍,也能抑制神经细胞退行性变性,这些效应可能构成了褪黑素对磷酸酯酶活性抑制所引起的记忆缺失的保护作用的基础。
小结
我们的研究发现:褪黑素不仅部分改善了花萼海绵诱癌素诱导的神经细丝的运输障碍及细胞退化样的改变,降低了骨架蛋白tau和神经细丝的过度磷酸化,而且改善了花萼海绵诱癌素诱导的空间记忆保留障碍。这些结果提示骨架蛋白的过度磷酸化可能在介导轴突运输障碍,轴突病变及空间记忆损伤等AD病理改变中起关键作用,褪黑素通过降低骨架蛋白的过度磷酸化部分逆转上述病理改变,提示褪黑素可能是有效治疗AD的药物。
Alzheimer's disease is characterized byβ-amyloid (Aβ) overproduction and tau hyperphosphorylation. The underlying mechanisms linking Aβand aberrant tau phosphorylation are poorly understood, and therefore there are no effective therapeutic measures for arresting the AD pathology. In our present study, we found that familial Alzheimer disease mutation with presenilin 1-L235P(leucine-to-proline mutation at codon 235 ) transgenic mice (PS-1 Tg) enhanced the generation of Aβ42, and significantly increased intracellular Aβ42 deposition in the brain of the aged Tg mice (16-17 months old). We also determined the alterations of phosphorylated tau and found that phosphorylation of tau at pSer396, Tau-1 (Ser198/199/202) and pSer404 epitopes was significantly increased in the aged Tg mice compared with the age-matched wild type mice (WT). Meanwhile, we detected an increased oxidative stress reaction as evidenced by elevated level of malondialdehyde (MDA) and decreased activity of superoxide dismutase (SOD) in the aged Tg mice, compared to the WT mice. We further detected the alterations in Akt-GSK-3βsignaling pathway and found a decreased phosphorylation of Akt, glycogen synthase kinase (GSK)-3βin the aged Tg mice. Exogenous supplementation of coenzyme Q10 (CoQ10), a powerful antioxidant and free radical scavenger, not only partially decreased MDA level and up-regulated the activity of SOD, but also arrested Aβ42 level and tau hyperphosphorylation, concurrently accompanied with a restoration of Akt-GSK-3βsignaling. These results suggest that the mutated PS-1 increases Aβ42 production and intracellular deposition selectively and tau hyperphosphorylation. The latter may be a consequence of intracellular overproduced Aβinduced-oxidative stress and the mechanisms may involve depression of oxidative stress-induced Akt-GSK-3βsignaling events. The neuroprotective effects of CoQ10 may act through its antioxidant property. Our data also indicate that the pathogenic role of the mutated PS-1 is upstream of the amyloid cascade and taupathy, and CoQ10 might be potentially useful for therapy of Alzheimer’s disease.
Part two
Melatonin Meliorates Calyculin A-induced Axonal Transport Defects and Spatial Memory Retention Impairment in Rats
We have recently found that melatonin protects SH-SY5Y neuroblastoma cells from calyculin A(CA)-induced neurofilament impairment and neurotoxicity. In the present study, we further investigated the in vivo effect of melatonin on spatial memory retention in rats by bilateral injection of CA, a potent and specific inhibitor of protein phosphatase-2A (PP-2A) and protein phosphatase-1 (PP-1) into hippocampus. We found that the supplementation of melatonin by intraperitoneal injection for 9 days before injecting CA not only significantly improves CA-induced memory retention deficits of the rats in the Morris Water-Maze Test, but also decreases hyperphosphorylation of neuronal cytoskeletal protein tau and neurofilaments. To further explore the underlying mechanisms of the protective effect of melatonin on spatial memory deficit in rats induced by CA, we analyzed the axonal transport by a time-lapse recording of pEGFP-labeled neurofilament-M (pEGFP-NF-M) subunit in live neuroblastoma N2a cells and found that melatonin partially reversed CA-induced impairment of transport of pEGFP- NF-M in the axon-like processes of the cells. In the meantime, we found by western blot that melatonin also decreased CA-induced hyperphosphorylation of cytoskeletal proteins. In addition, we explored the effect of melatonin on the morphological alteration of the cells during inhibition of the phosphatases by establishing a cell model showing steady outgrowth of axon-like cell processes and employed a stereological system to analyze the retraction of the processes. We found CA-treatment inhibited outgrowth of the cell processes and prolonged treatment with CA caused retraction of the processes and meanwhile, the early neurodegenerative varicosities were also obvious in the CA-treated cells, and the administration of melatonin significantly arrested these pathological alterations. These data suggest that melatonin not only meliorated impaired intracellular transport induced by suppression of PP-2A and PP-1, but also cell degeneration, which may underlie the basis of the effects of protection of melatonin on memory deficits induced by suppression of the phosphatases.
引文
1. Cruts M, Van Broeckhoven C. Presenilin mutations in Alzheimer's disease. Hum Mutat. 1998; 11(3):183-90.
2. Lleo A, Berezovska O, Growdon JH, Hyman BT. 2004. Clinical, pathological, and biochemical spectrum of Alzheimer disease associated with PS-1 mutations. Am J Geriatr Psychiatry. 2004 Mar-Apr; 12(2):146-56.
3. Shen J, Bronson RT, Chen DF, Xia W, Selkoe DJ, Tonegawa S. Skeletal and CNS defects in Presenilin-1-deficient mice. Cell. 1997 May 16; 89(4):629-39.
4. De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, Goate A, Kopan R. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature. 1999 Apr 8; 398(6727):518-22.
5. Wong PC, Zheng H, Chen H, Becher MW, Sirinathsinghji DJ, Trumbauer ME, Chen HY, Price DL, Van der Ploeg LH, Sisodia SS. Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm. Nature. 1997 May 15;387(6630):288-92
6. Selkoe DJ. Notch and presenilins in vertebrates and invertebrates: implications for neuronal development and degeneration. Curr Opin Neurobiol. 2000 Feb; 10(1):50-7.
7. De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature. 1998 Jan 22; 391(6665):387-90.
8. Takasugi N, Tomita T, Hayashi I, Tsuruoka M, Niimura M, Takahashi Y, Thinakaran G, Iwatsubo T. The role of presenilin cofactors in the gamma-secretase complex. Nature. 2003 Mar 27; 422(6930):438-41.
9. Vaucher E, Fluit P, Chishti MA, Westaway D, Mount HT, Kar S Object recognition memory and cholinergic parameters in mice expressing human presenilin 1 transgenes. Exp Neurol. 2002 Jun; 175(2):398-406.
10. Huang XG, Yee BK, Nag S, Chan ST, Tang F. Behavioral and neurochemical characterization of transgenic mice carrying the human presenilin-1 gene with orwithout the leucine-to-proline mutation at codon 235. Exp Neurol. 2003 Oct; 183(2):673-81.
11. Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T, Prada CM, Kim G, Seekins S, Yager D, Slunt HH, Wang R, Seeger M,Levey AI, Gandy SE, Copeland NG, Jenkins NA, Price DL, Younkin SG, Sisodia SS Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron. 1996 Nov; 17(5):1005-13.
12. Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-tur J, Hutton M, Buee L, Harigaya Y, Yager D,Morgan D, Gordon MN, Holcomb L, Refolo L, Zenk B, Hardy J, Younkin S. Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature. 1996 Oct 24; 383(6602):710-3.
13. Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, Johnson-Wood K, Lee M, Seubert P, Davis A, Kholodenko D, Motter R, Sherrington R, Perry B, Yao H, Strome R, Lieberburg I, Rommens J, Kim S, Schenk D, Fraser P, St George Hyslop P, Selkoe DJ. Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nat Med. 1997 Jan; 3(1):67-72.
14. Myers-Payne SC, Fontaine RN, Loeffler A, Pu L, Rao AM, Kier AB, Wood WG, Schroeder F Effects of chronic ethanol consumption on sterol transfer proteins in mouse brain. J Neurochem. 1996 Jan; 66(1):313-20.
15. Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J, Hutton M, Kukull W, Larson E, Levy-Lahad E, Viitanen M, Peskind E, Poorkaj P, Schellenberg G, Tanzi R, Wasco W, Lannfelt L, Selkoe D, Younkin S. Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat Med. 1996 Aug; 2(8):864-70.
16. Nakano Y, Kondoh G, Kudo T, Imaizumi K, Kato M, Miyazaki JI, Tohyama M, Takeda J, Takeda M. Accumulation of murine amyloidbeta42 in a gene-dosage-dependent manner in PS1 'knock-in' mice. Eur J Neurosci. 1999 Jul; 11(7):2577-81.
17. Chui DH, Tanahashi H, Ozawa K, Ikeda S, Checler F, Ueda O, Suzuki H, Araki W, Inoue H, Shirotani K, Takahashi K, Gallyas F, Tabira T. Transgenic mice withAlzheimer presenilin 1 mutations show accelerated neurodegeneration without amyloid plaque formation. Nat Med. 1999 May; 5(5):560-4.
18. Pigino G, Pelsman A, Mori H, Busciglio J. Presenilin-1 mutations reduce cytoskeletal association, deregulate neurite growth, and potentiate neuronal dystrophy and tau phosphorylation. J Neurosci. 2001 Feb 1; 21(3):834-42.
19. Gomez-Isla T, Wasco W, Pettingell WP, Gurubhagavatula S, Schmidt SD, Jondro PD, McNamara M, Rodes LA, DiBlasi T, Growdon WB, Seubert P, Schenk D, Growdon JH, Hyman BT, Tanzi RE. A novel presenilin-1 mutation: increased beta-amyloid and neurofibrillary changes. Ann Neurol. 1997 Jun; 41(6):809-13.
20. Guo Q, Sebastian L, Sopher BL, Miller MW, Ware CB, Martin GM, Mattson MP. Increased vulnerability of hippocampal neurons from presenilin-1 mutant knock-in mice to amyloid beta-peptide toxicity: central roles of superoxide production and caspase activity. J Neurochem. 1999 Mar; 72(3):1019-29.
21. Guo Q, Sopher BL, Furukawa K, Pham DG, Robinson N, Martin GM, Mattson MP. Alzheimer's presenilin mutation sensitizes neural cells to apoptosis induced by trophic factor withdrawal and amyloid beta-peptide: involvement of calcium and oxyradicals. J Neurosci. 1997 Jun 1; 17(11):4212-22.
22. Yankner BA, Duffy LK, Kirschner DA. Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science. 1990 Oct 12; 250(4978):279-82.
23. Behl C, Davis J, Cole GM, Schubert D. Vitamin E protects nerve cells from amyloid beta protein toxicity. Biochem Biophys Res Commun. 1992 Jul 31; 186(2):944-50.
24. Behl C, Davis JB, Lesley R, Schubert D. Hydrogen peroxide mediates amyloid beta protein toxicity. Cell. 1994 Jun 17; 77(6):817-27.
25. Butterfield DA, Hensley K, Harris M, Mattson M, Carney J. beta-Amyloid peptide free radical fragments initiate synaptosomal lipoperoxidation in a sequence-specific fashion: implications to Alzheimer's disease. Biochem Biophys Res Commun. 1994 Apr 29; 200(2):710-5.
26. Schubert D, Behl C, Lesley R, Brack A, Dargusch R, Sagara Y, Kimura H. Amyloid peptides are toxic via a common oxidative mechanism. Proc Natl Acad SciU S A. 1995 Mar 14; 92(6):1989-93.
27. Yankner BA. Mechanisms of neuronal degeneration in Alzheimer's disease. Neuron. 1996 May; 16(5):921-32.
28. Markesbery WR. Oxidative stress hypothesis in Alzheimer's disease. Free Radic Biol Med. 1997; 23(1):134-47.
29. Subbarao KV, Richardson JS, Ang LC Autopsy samples of Alzheimer's cortex show increased peroxidation in vitro. J Neurochem. 1990 Jul; 55(1):342-5.
30. Smith CD, Carney JM, Starke-Reed PE, Oliver CN, Stadtman ER, Floyd RA, Markesbery WR. Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease. Proc Natl Acad Sci U S A. 1991 Dec 1; 88(23):10540-3.
31. Mecocci P, MacGarvey U, Beal MF. Oxidative damage to mitochondrial DNA is increased in Alzheimer's disease. Ann Neurol. 1994 Nov; 36(5):747-51.
32. Mattson MP, Goodman Y Different amyloidogenic peptides share a similar mechanism of neurotoxicity involving reactive oxygen species and calcium. Brain Res. 1995 Apr 3; 676(1):219-24.
33. Mwangi S, Anitha M, Fu H, Sitaraman SV, Srinivasan S. Glial cell line-derived neurotrophic factor-mediated enteric neuronal survival involves glycogen synthase kinase-3beta phosphorylation and coupling with 14-3-3. Neuroscience. 2006 Nov 17; 143(1):241-51.
34. Anitha M, Chandrasekharan B, Salgado JR, Grouzmann E,Mwangi S, Sitaraman SV, Srinivasan S. Glial-derived neurotrophic factor modulates enteric neuronal survival and proliferation through neuropeptide Y. Gastroenterology. 2006 Oct; 131(4):1164-78.
35. Zachary I. Neuroprotective role of vascular endothelial growth factor: signalling mechanisms, biological function, and therapeutic potential. Neurosignals. 2005; 14(5):207-21.
36. Kretz A, Schmeer C, Tausch S, Isenmann S. Simvastatin promotes heat shock protein 27 expression and Akt activation in the rat retina and protects axotomized retinal ganglion cells in vivo. Neurobiol Dis. 2006 Feb; 21(2):421-30.
37. Noble W, Planel E, Zehr C, Olm V, Meyerson J, Suleman F, Gaynor K, Wang L,LaFrancois J, Feinstein B, Burns M, Krishnamurthy P, Wen Y, Bhat R, Lewis J, Dickson D, Duff K. Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci U S A. 2005 May 10; 102(19):6990-5.
38. Roberts MS, Woods AJ, Dale TC, Van Der Sluijs P, Norman JC. Protein kinase B/Akt acts via glycogen synthase kinase 3 to regulate recycling of alpha v beta 3 and alpha 5 beta 1 integrins. Mol Cell Biol. 2004 Feb; 24(4):1505-15.
39. Chan PH. Mitochondrial dysfunction and oxidative stress as determinants of cell death/survival in stroke. Ann N Y Acad Sci. 2005 May;1042:203-9.
40. Chong ZZ, Li F, Maiese K. Oxidative stress in the brain: novel cellular targets that govern survival during neurodegenerative disease. Prog Neurobiol. 2005 Feb; 75(3):207-46.
41. Taylor JM, Ali U, Iannello RC, Hertzog P, Crack PJ. Diminished Akt phosphorylation in neurons lacking glutathione peroxidase-1 (Gpx1) leads to increased susceptibility to oxidative stress-induced cell death. J Neurochem. 2005 Jan; 92(2):283-93.
42. Xia CF, Yin H, Borlongan CV, Chao J, Chao L. Adrenomedullin gene delivery protects against cerebral ischemic injury by promoting astrocyte migration and survival. Hum Gene Ther. 2004 Dec; 15(12):1243-54 .
43. Ernster L, Dallner G. Biochemical, physiological and medical aspects of ubiquinone function. Biochim Biophys Acta. 1995 May 24; 1271(1):195-204
44. Noack H, Kube U, Augustin W. Relations between tocopherol depletion and coenzyme Q during lipid peroxidation in rat liver mitochondria. Free Radic Res. 1994 Jun; 20(6):375-86.
45. Forsmark-Andree P, Lee CP, Dallner G, Ernster L. Lipid peroxidation and changes in the ubiquinone content and the respiratory chain enzymes of submitochondrial particles. Free Radic Biol Med. 1997; 22(3):391-400.
46. Beyer RE. An analysis of the role of coenzyme Q in free radical generation and as an antioxidant. Biochem Cell Biol. 1992 Jun; 70(6):390-403.
47. Modi K, Santani DD, Goyal RK, Bhatt PA. Effect of coenzyme Q10 on catalase activity and other antioxidant parameters in streptozotocin-induced diabetic rats.Biol Trace Elem Res. 2006 Jan; 109(1):25-34.
48. Marubayashi S, Dohi K, Ochi K, Kawasaki T. Protective effects of free radical scavenger and antioxidant administration on ischemic liver cell injury. Transplant Proc. 1987 Feb; 19(1 Pt 2):1327-8.
49. Matthews RT, Yang L, Browne S, Baik M, Beal MF. Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects. Proc Natl Acad Sci U S A. 1998 Jul 21; 95(15):8892-7.
50. Kamzalov S, Sumien N, Forster MJ, Sohal RS. Coenzyme Q intake elevates the mitochondrial and tissue levels of Coenzyme Q and alpha-tocopherol in young mice. J Nutr. 2003 Oct; 133(10):3175-80.
51. Shults CW, Oakes D, Kieburtz K, Beal MF, Haas R, Plumb S, Juncos JL, Nutt J, Shoulson I, Carter J, Kompoliti K, Perlmutter JS, Reich S, Stern M, Watts RL, Kurlan R, Molho E, Harrison M, Lew M; Parkinson Study Group. Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol. 2002 Oct; 59(10):1541-50.
52. Ferrante RJ, Andreassen OA, Dedeoglu A, Ferrante KL, Jenkins BG, Hersch SM, Beal MF. Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington's disease. J Neurosci. 2002 Mar 1; 22(5):1592-9.
53. Smith KM, Matson S, Matson WR, Cormier K, Del Signore SJ, Hagerty SW, Stack EC, Ryu H, Ferrante RJ. Dose ranging and efficacy study of high-dose coenzyme Q10 formulations in Huntington's disease mice. chim Biophys Acta. 2006 Jun; 1762(6):616-26
54. Traynor BJ, Bruijn L, Conwit R, Beal F, O'Neill G, Fagan SC, Cudkowicz ME. Neuroprotective agents for clinical trials in ALS: a systematic assessment. Neurology. 2006 Jul 11; 67(1):20-7.
55. Wu SS, Frucht SJ. Treatment of Parkinson's disease : what's on the horizon? CNS Drugs. 2005; 19(9):723-43.
56. Beal MF, Henshaw DR, Jenkins BG, Rosen BR, Schulz JB. Coenzyme Q10 and nicotinamide block striatal lesions produced by the mitochondrial toxin malonate. Ann Neurol. 1994 Dec; 36(6):882-8.
57. Koroshetz WJ, Jenkins BG, Rosen BR, Beal MF. Energy metabolism defects inHuntington's disease and effects of coenzyme Q10. Ann Neurol. 1997 Feb; 41(2):160-5.
58. McCarthy S, Somayajulu M, Sikorska M, Borowy-Borowski H, Pandey S.Paraquat induces oxidative stress and neuronal cell death; neuroprotection by water-soluble Coenzyme Q10. Toxicol Appl Pharmacol. 2004 Nov 15; 201(1):21-31.
59. Moreira PI, Santos MS, Sena C, Nunes E, Seica R, Oliveira CR. CoQ10 therapy attenuates amyloid beta-peptide toxicity in brain mitochondria isolated from aged diabetic rats. Exp Neurol. 2005 Nov; 196(1):112-9.
60. Ono K, Hasegawa K, Naiki H, Yamada M. Preformed beta-amyloid fibrils are destabilized by coenzyme Q10 in vitro. Biochem Biophys Res Commun. 2005 Apr 29; 330(1):111-6.
61. Li G, Zou L, Jack CR Jr, Yang Y, Yang ES. Neuroprotective effect of Coenzyme Q10 on ischemic hemisphere in aged mice with mutations in the amyloid precursor protein. Neurobiol Aging. 2006 Jun 26.
62. Grieb P, Ryba MS, Sawicki J, Chrapusta SJ. Oral coenzyme Q10 administration prevents the development of ischemic brain lesions in a rabbit model of symptomatic vasospasm. Acta Neuropathol (Berl). 1997 Oct; 94(4):363-8.
63. Ostrowski RP. Effect of coenzyme Q10 (CoQ10) on superoxide dismutase activity in ET-1 and ET-3 experimental models of cerebral ischemia in the rat. Folia Neuropathol. 1999; 37(4):247-51.
64. Tsukahara Y, Wakatsuki A, Okatani Y. Antioxidant role of endogenous coenzyme Q against the ischemia and reperfusion-induced lipid peroxidation in fetal rat brain. Acta Obstet Gynecol Scand. 1999 Sep; 78(8):669-74.
65. Campion D, Brice A, Dumanchin C, Puel M, Baulac M, De La Sayette V, Hannequin D, Duyckaerts C, Michon A, Martin C, Moreau V, Penet C, Martinez M, Clerget-Darpoux F, Agid Y, Frebourg T. A novel presenilin 1 mutation resulting in familial Alzheimer's disease with an onset age of 29 years. Neuroreport. 1996 Jul 8; 7(10):1582-4.
66. Rogaeva EA, Fafel KC, Song YQ, Medeiros H, Sato C, Liang Y, Richard E, Rogaev EI, Frommelt P, Sadovnick AD, Meschino W, Rockwood K, Boss MA, Mayeux R, St George-Hyslop P. Screening for PS1 mutations in a referral-basedseries of AD cases: 21 novel mutations. Neurology. 2001 Aug 28; 57(4):621-5.
67. Butterfield DA. Amyloid beta-peptide (1-42)-induced oxidative stress and neurotoxicity: implications for neurodegeneration in Alzheimer's disease brain. A review. Free Radic Res. 2002 Dec; 36(12):1307-13.
68. Boyd-Kimball D, Sultana R, Mohmmad-Abdul H, Butterfield DA. Rodent Abeta(1-
42) exhibits oxidative stress properties similar to those of human Abeta(1-42): Implications for proposed mechanisms of toxicity. Alzheimers Dis. 2004 Oct; 6(5):515-25.
69. Mohmmad Abdul H, Sultana R, Keller JN, St Clair DK, Markesbery WR, Butterfield DA. Mutations in amyloid precursor protein and presenilin-1 genes increase the basal oxidative stress in murine neuronal cells and lead to increased sensitivity to oxidative stress mediated by amyloid beta-peptide (1-42), HO and kainic acid: implications for Alzheimer's disease. J Neurochem. 2006 Mar; 96(5):1322-35.
70. Tamagno E, Parola M, Bardini P, Piccini A, Borghi R, Guglielmotto M, Santoro G, Davit A, Danni O, Smith MA, Perry G, Tabaton M. Beta-site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress-activated protein kinases pathways. Neurochem. 2005 Feb; 92(3):628-36.
71. Tong Y, Zhou W, Fung V, Christensen MA, Qing H, Sun X, Song W. Oxidative stress potentiates BACE1 gene expression and Abeta generation. J Neural Transm. 2005 Mar; 112(3):455-69.
72. Wang ZF, Li HL, Li XC, Zhang Q, Tian Q, Wang Q, Xu H, Wang JZ. Effects of endogenous beta-amyloid overproduction on tau phosphorylation in cell culture. J Neurochem. 2006 Aug; 98(4):1167-75.
73. Chong ZZ, Li F, Maiese K. Group I metabotropic receptor neuroprotection requires Akt and its substrates that govern FOXO3a, Bim, and beta-catenin during oxidative stress. Curr Neurovasc Res. 2006 May; 3(2):107-17.
74. Koh SH, Jung B, Song CW, Kim Y, Kim YS, Kim SH. 15-Deoxy-delta12,14-prostaglandin J2, a neuroprotectant or a neurotoxicant? Toxicology. 2005 Dec 15; 216(2-3):232-43.
75. Kilic U, Kilic E, Reiter RJ, Bassetti CL, Hermann DM. Signal transductionpathways involved in melatonin-induced neuroprotection after focal cerebral ischemia in mice. J Pineal Res. 2005 Jan; 38(1):67-71.
76. Li G, Zou LY, Cao CM, Yang ES. Coenzyme Q10 protects SHSY5Y neuronal cells from beta amyloid toxicity and oxygen-glucose deprivation by inhibiting the opening of the mitochondrial permeability transition pore. Biofactors. 2005; 25(1-4):97-107.
1. Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology. 1992 Mar; 42(3 Pt 1):631-9.
2. Feany MB, Dickson DW. Neurodegenerative disorders with extensive tau pathology: a comparative study and review. Ann Neurol. 1996 Aug; 40(2):139-48.
3. Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, Wisniewski HM. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem. 1986 May 5; 261(13):6084-9.
4. Lee VM, Balin BJ, Otvos L Jr, Trojanowski JQ. A68: a major subunit of paired helical filaments and derivatized forms of normal Tau. Science.1991 Feb 8; 251(4994):675-8.
5. Goedert M, Spillantini MG, Cairns NJ, Crowther RA. Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron. 1992 Jan; 8(1):159-68.
6. Kanemaru K, Takio K, Miura R, Titani K, Ihara Y. Fetal-type phosphorylation of the tau in paired helical filaments J Neurochem. 1992 May; 58(5):1667-75.
7. Sternberger NH, Sternberger LA, Ulrich J. Aberrant neurofilament phosphorylation in Alzheimer disease Proc Natl Acad Sci U S A. 1985 Jun;82(12):4274-6.
8. Wang J, Tung YC, Wang Y, Li XT, Iqbal K, Grundke-Iqbal I. Hyperphosphorylation and accumulation of neurofilament proteins in Alzheimer disease brain and in okadaic acid-treated SY5Y cells. FEBS Lett. 2001 Oct 19; 507(1):81-7.
9. Hu YY, He SS, Wang XC, Duan QH, Khatoon S, Iqbal K, Grundke-Iqbal I, Wang JZ. Elevated levels of phosphorylated neurofilament proteins in cerebrospinal fluid of Alzheimer disease patients. Neurosci Lett. 2002 Mar 8; 320(3):156-60.
10. Tian Q, Wang J. Role of serine/threonine protein phosphatase in Alzheimer's disease. Neurosignals. 2002 Sep-Oct; 11(5):262-9.
11. He J, Yamada K, Zou LB, Nabeshima T. Spatial memory deficit and neurodegeneration induced by the direct injection of okadaic acid into the hippocampus in rats. J Neural Transm. 2001; 108(12):1435-43.
12. Sun L, Liu SY, Zhou XW, Wang XC, Liu R, Wang Q, Wang JZ. Inhibition of protein phosphatase 2A- and protein phosphatase 1-induced tau hyperphosphorylation and impairment of spatial memory retention in rats. Neuroscience. 2003; 118(4):1175-82.
13. Arendt T, Holzer M, Fruth R, Bruckner MK, Gartner U. Paired helical filament-like phosphorylation of tau, deposition of beta/A4-amyloid and memory impairment in rat induced by chronic inhibition of phosphatase 1 and 2A. Neuroscience. 1995 Dec; 69(3):691-8.
14. Sanchez MP, Alvarez-Tallada V, Avila J. The microtubule-associated protein tau in neurodegenerative diseases. Tauopathies. Rev Neurol. 2001 Jul 16-31; 33(2):169-77.
15. Sang H, Lu Z, Li Y, Ru B, Wang W, Chen J. Phosphorylation of tau by glycogen synthase kinase 3beta in intact mammalian cells influences the stability of microtubules. Neurosci Lett. 2001 Oct 26; 312(3):141-4.
16. Lee MK, Cleveland DW. Neuronal intermediate filaments. Annu Rev Neurosci. 1996; 19:187-217.
17. de Waegh SM, Lee VM, Brady ST. Local modulation of neurofilament phosphorylation, axonal caliber, and slow axonal transport by myelinating Schwann cells. Cell. 1992 Feb 7; 68(3):451-63.
18. Shea TB, Paskevich PA, Beermann ML. The protein phosphatase inhibitor okadaic acid increases axonal neurofilaments and neurite caliber, and decreases axonal microtubules in NB2a/d1 cells. J Neurosci Res. 1993 Aug 1; 35(5):507-21.
19. Hoffman PN, Thompson GW, Griffin JW, Price DL. Changes in neurofilament transport coincide temporally with alterations in the caliber of axons in regenerating motor fibers. J Cell Biol. 1985 Oct; 101(4):1332-40.
20. Mudher A, Shepherd D, Newman TA, Mildren P, Jukes JP, Squire A, Mears A, Drummond JA, Berg S, MacKay D, Asuni AA, Bhat R, Lovestone S. GSK-3beta inhibition reverses axonal transport defects and behavioural phenotypes in Drosophila. Mol Psychiatry. 2004 May; 9(5):522-30.
21. Brzezinski A. Melatonin in humans. N Engl J Med. 1997 Jan 16; 336(3):186-95.
22. Wang DL, Ling ZQ, Cao FY, Zhu LQ, Wang JZ. Melatonin attenuates isoproterenol-induced protein kinase A overactivation and tau hyperphosphorylation in rat brain. J Pineal Res. 2004 Aug; 37(1):11-6.
23. Wang YP, Li XT, Liu SJ, Zhou XW, Wang XC, Wang JZ. Melatonin ameliorated okadaic-acid induced Alzheimer-like lesions. Acta Pharmacol Sin. 2004 Mar; 25(3):276-80.
24. Liu SJ, Wang JZ. Alzheimer-like tau phosphorylation induced by wortmannin in vivo and its attenuation by melatonin. Acta Pharmacol Sin. 2002 Feb; 23(2):183-7.
25. Li SP, Deng YQ, Wang XC, Wang YP, Wang JZ. Melatonin protects SH-SY5Y neuroblastoma cells from calyculin A-induced neurofilament impairment and neurotoxicity. J Pineal Res. 2004 Apr; 36(3):186-91.
26. Wang JZ, Wang ZF. Role of melatonin in Alzheimer-like neurodegeneration. Acta Pharmacol Sin. 2006 Jan; 27(1):41-9.
27. Paxinos G, Watson C, Pennisi M, Topple A. Bregma, lambda and the interaural midpoint in stereotaxic surgery with rats of different sex, strain and weight. J Neurosci Methods. 1985 Apr; 13(2):139-43.
28. Bourtchuladze R, Frenguelli B, Blendy J,Cioffi D, Schutz G, Silva AJ. Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell. 1994 Oct 7; 79(1):59-68.
29. Guzowski JF, McGaugh JL. Antisense oligodeoxynucleotide-mediated disruption of hippocampal cAMP response element binding protein levels impairs consolidation of memory for water maze training. Proc Natl Acad Sci U S A. 1997 Mar 18; 94(6):2693-8.
30. Gong CX, Singh TJ, Grundke-Iqbal I, Iqbal K. Phosphoprotein phosphatase activities in Alzheimer disease brain. J Neurochem. 1993 Sep; 61(3):921-7.
31. Sontag E, Nunbhakdi-Craig V, Lee G, Brandt R, Kamibayashi C, Kuret J, White CL 3rd, Mumby MC, Bloom GS. Molecular interactions among protein phosphatase 2A, tau, and microtubules. Implications for the regulation of tau phosphorylation and the development of tauopathies. J Biol Chem. 1999 Sep 3; 274(36):25490-8.
32. Wang JZ, Grundke-Iqbal I, Iqbal K. Restoration of biological activity of Alzheimer abnormally phosphorylated tau by dephosphorylation with protein phosphatase-2A, -2B and -1. Brain Res Mol Brain Res. 1996 Jun; 38(2):200-8.
33. Yamamoto T, Yuyama K, Nakamura K, Kato T, Yamamoto H. Kinetic characterization of the nitric oxide toxicity for PC12 cells: effect of half-life time of NO release. Eur J Pharmacol. 2000 May 26; 397(1):25-33.
34. Wang JZ, Gong CX, Zaidi T, Grundke-Iqbal I, Iqbal K. Dephosphorylation of Alzheimer paired helical filaments by protein phosphatase-2A and -2B. J Biol Chem. 1995 Mar 3; 270(9):4854-60.
35. Liu F, Grundke-Iqbal I, Iqbal K, Gong CX. Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation. Eur J Neurosci. 2005 Oct; 22(8):1942-50.
36. Tanaka T, Zhong J, Iqbal K, Trenkner E, Grundke-Iqbal I. The regulation of phosphorylation of tau in SY5Y neuroblastoma cells: the role of protein phosphatases. FEBS Lett. 1998 Apr 17; 426(2):248-54 .
37. Gong CX, Lidsky T, Wegiel J, Zuck L, Grundke-Iqbal I, Iqbal K. Phosphorylation of microtubule-associated protein tau is regulated by protein phosphatase 2A in mammalian brain. Implications for neurofibrillary degeneration in Alzheimer's disease. J Biol Chem. 2000 Feb 25; 275(8):5535-44.
38. Cash AD, Aliev G, Siedlak SL, Nunomura A, Fujioka H, Zhu X, Raina AK, Vinters HV, Tabaton M, Johnson AB, Paula-Barbosa M, Avila J, Jones PK, Castellani RJ, Smith MA, Perry G. Microtubule reduction in Alzheimer's disease and aging is independent of tau filament formation. Am J Pathol. 2003 May; 162(5):1623-7.
39. Stokin GB, Lillo C, Falzone TL, Brusch RG, Rockenstein E, Mount SL, Raman R, Davies P,Masliah E, Williams DS, Goldstein LS. Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease. Science. 2005 Feb 25; 307(5713):1282-8.
40. Smith DH, Chen XH, Iwata A, Graham DI. Amyloid beta accumulation in axons after traumatic brain injury in humans. J Neurosurg. 2003 May; 98(5):1072-7.
41. Yagishita S. Morphological investigations on axonal swellings and spheroids in various human diseases. Virchows Arch A Pathol Anat Histol. 1978 Jun 15; 378(3):181-97.
42. Biernat J, Gustke N, Drewes G, Mandelkow EM, Mandelkow E. Phosphorylation of Ser262 strongly reduces binding of tau to microtubules: distinction between PHF-like immunoreactivity and microtubule binding. Neuron. 1993 Jul; 11(1):153-63.
43. Davies CA, Mann DM, Sumpter PQ, Yates PO. A quantitative morphometric analysis of the neuronal and synaptic content of the frontal and temporal cortex in patients with Alzheimer's disease. J Neurol Sci. 1987 Apr; 78(2):151-64.
44. DeKosky ST, Scheff SW. Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann Neurol. 1990 May; 27(5):457-64.
45. Hall GF, Yao J. Neuronal morphology, axonal integrity, and axonal regeneration in situ are regulated by cytoskeletal phosphorylation in identified lamprey central neurons. Microsc Res Tech. 2000 Jan 1; 48(1):32-46.
46. Jung C, Yabe JT, Lee S, Shea TB. Hypophosphorylated neurofilament subunits undergo axonal transport more rapidly than more extensively phosphorylated subunits in situ. Cell Motil Cytoskeleton. 2000 Oct; 47(2):120-9.
47. Hirokawa N, Takeda S. Gene targeting studies begin to reveal the function of neurofilament proteins. J Cell Biol. 1998 Oct 5; 143(1):1-4.
48. Hoffman PN, Griffin JW, Price DL. Control of axonal caliber by neurofilament transport. J Cell Biol. 1984 Aug; 99(2):705-14.
49. Ren QG, Liao XM, Wang ZF, Qu ZS, Wang JZ. The involvement of glycogen synthase kinase-3 and protein phosphatase-2A in lactacystin-induced tau accumulation. FEBS Lett. 2006 May 1; 580(10):2503-11.
1. Dallner G, Stocker R, Coenzyme Q. In: Encyclopedia of dietary supplements. New York: Marcel Dekker; 2005. pp. 121–131. A comprehensive yet synthetic review highlighting both the biochemical aspects and clinical implications of coenzyme Q.
2. Groneberg DA, Kindermann B, Althammer M, et al. Coenzyme Q10 affects expression of genes involved in cell signalling, metabolism and transport in human CaCo-2 cells. Int J Biochem Cell Biol 2005; 37:1208–1218. The findings of this paper are innovative and represent the first demonstration that CoQ10 affects gene expression in vitro.
3. M. Flint Beal. Therapeutic Effects of Coenzyme Q10 in Neurodegenerative Diseases. METHODS IN ENZYMOLOGY 2004; 382: 473-487.
4. Crane FL, Hatefi Y, Lester RL, Widmer C (1957) Isolation of a quinone from beef heart mitochondria. Biochim Biophys Acta 25:220–221.
5. Kuglstatter A, Miksovska J, Sebban P, Fritzsch G. Structure of the photosynthetic reaction centre from Rhodobacter sphaeroides reconstituted with anthraquinone as primary quinone Q(A). FEBS Lett. 2000 Apr 21; 472(1):114-116.
6. Lenaz G (ed):“Coenzyme Q.”Chichester: Wiley, 1985.
7. McAuley KE, Fyfe PK, Ridge JP, Cogdell RJ, Isaacs NW, Jones MR. Ubiquinone binding, ubiquinone exclusion, and detailed cofactor conformation in a mutant bacterial reaction center. Biochemistry. 2000 Dec 12; 39(49):15032-43.
8. Schmid R, Gerloff DL.Functional properties of the alternative NADH:ubiquinone oxidoreductase from E. coli through comparative 3-D modelling. FEBS Lett. 2004 Dec 3; 578(1-2):163-8.
9. Kalen A, Norling B, Appelkvist EL, Dallner G: Ubiquinone biosynthesis by the microsomal fraction of rat liver. Biochim Biophys Acta 926:70–78, 1987.
10. Cramer WA, Soriano GM: Energy transduction function of the quinone reactions in cytochrome bc complexes. Biofactors 9:81–86, 1999.
11. Brandt U: Proton translocation in the respiratory chain involving ubiquinone—a hypothetical semiquinone switch mechanism for complex I. Biofactors 9:95–102, 1999.
12. Yu CA, Zhang K-P, Deng H, Xia D, Klm H, Deisenhofer J, Yu L: Structure and reaction mechanisms of the multifunctional mitochondrial cytochrome bc1 complex. Biofactors 9:103–110, 1999.
13. Takahashi T, Okamoto T, Mori K, Sayo H, Kishi T: Distribution of ubiquinone and ubiquinol homologues in rat tissues and subcellular fraction. Lipids 28:803–809, 1993.
14. Quinn PJ, Fabisiak JP, Kagan VE: Expansion of the antioxidant function of vitamin E by coenzyme Q. Biofactors 9:149–154, 1999.
15. Takahashi T, Okamoto T, Kishi T: Characterization of NADPH dependent ubiquinone reductase activity in rat liver cytosol. J Biochem 119:256–263, 1996.
16. Villalba JM, Navas P: Plasma membrane redox system in the control of stress induced apoptosis. Antioxid Redox Signal 2:213–230, 2000.
17. Crane FL: New functions for coenzyme Q. Protoplasma, 213:127–133, 2000.
18. Poon WW, Do TQ, Marbois BN, Clarke CF: Sensitivity to treatment with polyunsaturated fatty acids is a general characteristic of the ubiquinone-deficient yeast coq mutants. Mol Aspect Med 18(S):121–128, 1997.
19. McLennan H, Degli Esposti M: The contribution of mitochondrial respiratory complexes to the production of reactive oxygen species. J Bioenerg Biomemb 32:153–162, 2000.
20. Kaltschmidt B, Sparna T, Kaltschmidt C: Activation of NFKB by reactive oxygen intermediates in the nervous system. Antioxid Redox Signal 1:129–144, 1999.
21. Morad M, Suzuki YJ: Redox regulation of cardiac muscle calcium signaling. Antioxid Redox Signal 2:65–71, 2000.
22. Schipper HM. Brain iron deposition and the free radical-mitochondrial theory of ageing. Ageing Res Rev 2004; 3: 265-301.
23. Kidd PM. A review of nutrients and botanicals in the integrative management of cognitive dysfunction. Altern Med Rev 1999; 4: 144-161.
24. Gary EG, Hsueh-Meei H. Oxidative stress in Alzheimer’s disease. Neurobiol Aging 2005; 26:575–8.
25. Sullivan PG, Brown MR. Mitochondrial aging and dysfunction in Alzheimer’s disease. Progr Neuropsychopharmacol Biol Psychiatry 2005; 29: 407-410.
26. Gabuzda, D., Busciglio, J., Chen, L. B., Matsudaira, P., and Yankner, B. A. (1994). J. Biol. Chem. 269, 13623–13628.
27. Ohyagi, Y., Yamada, T., Nishioka, K., Clarke, N. J., Tomlinson, A. J., Naylor, S., Nakabeppu, Y., Kira, J., and Younkin, S. G. (2000). Neuroreport 11, 167–171.
28. Tamagno, E., Bardini, P., Obbili, A., Vitali, A., Borghi, R., Zaccheo, D.,Pronzato, M. A., Danni, O., Smith, M. A., Perry, G., and Tabaton, M. (2002). Neurobio. Dis. 10, 279–288.
29. Drake, J., Link, C. D., and Butterfield, D. A. (2003). Neurobiol. Aging 24, 415–420.
30. S?derberg, M.; Edlund, C.; Alafuzoff. I.; Kristensson, K.; Dallner,G. J. Neurochem., 1992, 59, 1646.
31. Barja G. Free radicals and aging. Trends Neurosci 2004; 27: 595-600.
32. K. S. Echtay, E. Winkler, and M. Klingenberg, Nature 408, 609 (2000).
33. K. Echtay, E. Winkler, K. Frischmuth, and M. Klingenberg, Proc. Natl. Acad. Sci. USA 98, 1416 (2001).
34. D. Ricquier and F. Bouillaud, Biochem. J. 345, 161 (2000).
35. P. G. Sullivan, C. Dube, K. Dorenbos, O. Steward, and T. Z. Baram, Ann. Neurol., published online (2003).
36. L. Walter, V. Nogueira, X. Leverve, M. P. Heitz, P. Bernardi, and E. Fontaine, J. Biol. Chem. 275, 29521 (2000).
37. E. Fontaine, F. Ichas, and P. Bernardi, J. Biol. Chem. 273, 25734 (1998).
38. Geng Li , Liangyu Zou, Clifford R. Jack Jr. ,Yihong Yang , Edward S. Yang. Neuroprotective effect of Coenzyme Q10 on ischemic hemisphere in aged mice with mutations in the amyloid precursor protein. Neurobiology of Aging 2006.
39. Matthews RT, Yang L, Browne S, Baik M, Beal MF. Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects. Proc Natl Acad Sci USA 1998; 95(15):8892–7.
40. Ostrowski RP. Effect of coenzyme Q (10) on biochemical and morphological changes in experimental ischemia in the rat brain. Brain Res Bull 2000; 53(4):399–407.
41. Tauheed Ishrat , M. Badruzzaman Khan, Md. Nasrul Hoda, Seema Yousuf et al. Coenzyme Q10 modulates cognitive impairment against intracerebroventricularinjection of streptozotocin in rats. Behav Brain Res. 2006; 171(1):9-16.
42. Beal MF. Mitochondrial dysfunction and oxidative damage in Alzheimer’s and Parkinson’s diseases and coenzyme Q10 as a potential treatment. J Bioenerg Biomembr 2004; 36:381–386.
43. Winkler-Stuck K, Widemann FR, Wallesch CW, Kunz WS. Effect of coenzyme Q10 on the mitochondrial function of skin fibroblasts from Parkinson patients. J Neurol Sci 2004; 220:41–48.
44. Janetzky, B., Hauck, S., Youdim, M. B., Riederer, P., Jellinger, K., Pantucek, F., Zochling, R., Boissl, K. W., Reichmann, H. (1994). Neurosci. Lett. 169, 126–128.
45. Betarbet, R., Sherer, T. B., MacKenzie, G., Garcia-Osuna, M., Panov, A. V., and Greenamyre, J. T. (2000). Nat. Neurosci. 3, 1301–1306.
46. Eriksen JL, Wszolek Z, Petrucelli L. Molecular pathogenesis of Parkinson disease. Arch Neurol 2005; 62:353-357.
47. Ikebe, S.-I., Tanaka, M., Ozawa, T., 1995. Point mutations of mitochondrial genome in Parkinson’s disease. Mol. Brain Res. 28, 281–295.
48. Gu, M., Cooper, J. M., Taanman, J. W., and Schapira, A. H. V. (1998). Ann. Neurol. 44, 177–186.
49. Kirchner, S.C., Hallagan, S.E., Farin, F.M., Dilley, J., Costa-Mallen, P., Smith-Weller, T., Franklin, G.M., Swanson, P.D., Checkoway, H., 2000. Mitochondrial ND1 sequence analysis and association of the T4216C mutation with Parkinson’s disease. Neurotoxicology 21 (4), 441–446.
50. Thyagarajan, D., Bressman, S., Bruno, C., Przedborski, S., Shanske, S., Lynch, T., Fahn, S., and DiMauro, S. (2000). Ann. Neurol. 48, 730–736.
51. Masashi Tanaka (2002). Mitochondrial genotypes and cytochrome b variants associated with longevity or Parkinson’s disease. J Neurol. 249 Suppl 2:II11-8/
52. Matsubara, T.; Azuma, T.; Yoshida, S.; Yamagami, T. In: Biomedical and clinical aspects of coenzyme Folkers, Q.K.; Littarru, G.P.; Yamagami, T. Eds. Elsevier Science Publishers, 1991, pp.159-166.
53. Molina, J.A.; de Bustos, F.; Ortiz, S.; Del Ser, T.; Seijo, M.; Benito-Léon, J.; Oliva, J.M.; Pérez, S.; Manzanares, J. Neural. Transm., 2002, 109, 1195.
54. Somayajulu M, McCarthy S, Hung M, et al. Role of mitochondria in neuronal celldeath induced by oxidative stress: neuroprotection by coenzyme Q10. Neurobiol Dis 2005; 18:618–627.
55. M. Flint Beal. Coenzyme Q10 administration and its potential for treatment of neurodegenerative diseases. BioFactors 1999; 9: 261–266.
56. Shults CW, Oakes D, Kieburtz K, et al. Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol 2002; 59:1541–1550.
57. Shults CW, Flint Beal M, Song D, Fontaine D. Pilot trial of high dosages of coenzyme Q10 in patients with Parkinson’s disease. Exp Neurol 2004; 188:491–494.
58. Gille G, Hung ST, Reichmann H, Rausch WD. Oxidative stress to dopaminergic neurons as models of Parkinson’s disease. Ann N Y Acad Sci 2004; 1018:533–540.
59. Sharma SK, El Refaey H, Ebadi M. Complex-1 activity and 18F-DOPA uptake in genetically engineered mouse model of Parkinson’s disease and the neuroprotective role of coenzyme Q10. Brain Res Bull. 2006 Jun 15; 70(1):22-32.
60. Sohmiya M, Tanaka M, Tak NW, et al. Redox status of plasma coenzyme Q10 indicates elevated systemic oxidative stress in Parkinson’s disease. J Neurol Sci 2004; 223:161–166.
61. Gardian G, Vecsei L. Huntington’s disease: pathomechanism and therapeutic perspectives. J Neural Transm 2004; 111: 1485-1494.
62. Goebel, H.H.; Heipertz, R.; Scholz, W.; Iqbal, K.; Tellez-Nagel, I. Neurology, 1978, 28, 23.
63. Brouillet, E.; Hantraye, P.; Ferrante, R.J.; Dolan, R.; Leroy-Willig, A.; Kowall, N.W.; Beal, M.F. Proc. Natl. Acad. Sci. USA, 1995, 92, 7105.
64. Tabrizi SJ, Workman J, Hart PE, et al. Mitochondrial dysfunction and free radical damage in the Huntington R6/2 transgenic mouse. Ann Neurol. 2000 Jan; 47(1):80-6.
65. Browne, S.E.; Bowling, A.C.; MacGarvey, U.; Baik, M.J.; Berger, S.C.; Muqit, M.M.; Bird, E.D.; Beal, M.F. Ann. Neurol., 1997, 41,646.
66. Gu, M.; Gash, M.T.; Mann, V.M.; Javoy-Agid, F.; Cooper, J.M.; Schapira, A.H. Ann. Neurol., 1996, 39, 385.
67. Koroshetz WJ, Jenkins BG, Rosen BR, Beal MF. Energy metabolism defects in Huntington’s disease and effects of coenzyme Q10. Ann Neurol 1997; 41:160-165.
68. Panov, A.V.; Gutekunst, C.A.; Leavitt, B.R.; Hayden, M.R.; Burke, J.R.; Strittmatter, W.J.; Greenamyre, J.T. Nat. Neurosci., 2002, 5,731.
69. Weydt P, Pineda VV, Torrence AE, et al.Thermoregulatory and metabolic defects in Huntington's disease transgenic mice implicate PGC-1alpha in Huntington's disease neurodegeneration. Cell Metab. 2006 Nov; 4(5):349-62.
70. Cui L, Jeong H, Borovecki F, Parkhurst CN, Tanese N, Krainc D. Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell. 2006 Oct 6; 127(1):59-69.
71. Beal, M.F.; Henshaw, D.R.; Jenkins, B.G.; Rosen, B.R.; Schulz, J.B. Ann. Neurol., 1994, 36, 882.
72. Ferrante RJ, Andreassen OA, Dedeoglu A, Ferrante KL, et al. Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington's disease. J Neurosci. 2002 Mar 1; 22(5):1592-9.
73. Andrich J, Saft C, Gerlach M. Coenzyme Q10 serum levels in Huntington's disease. J Neural Transm Suppl. 2004; (68):111-6.
74. Smith KM, Matson S, Matson WR, Cormier K et al. Dose ranging and efficacy study of high-dose coenzyme Q10 formulations in Huntington's disease mice. Biochim Biophys Acta. 2006 Jun; 1762(6):616-26.
2. Lleo A, Berezovska O, Growdon JH, Hyman BT. 2004. Clinical, pathological, and biochemical spectrum of Alzheimer disease associated with PS-1 mutations. Am J Geriatr Psychiatry. 2004 Mar-Apr; 12(2):146-56.
3. Shen J, Bronson RT, Chen DF, Xia W, Selkoe DJ, Tonegawa S. Skeletal and CNS defects in Presenilin-1-deficient mice. Cell. 1997 May 16; 89(4):629-39.
4. De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, Goate A, Kopan R. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature. 1999 Apr 8; 398(6727):518-22.
5. Wong PC, Zheng H, Chen H, Becher MW, Sirinathsinghji DJ, Trumbauer ME, Chen HY, Price DL, Van der Ploeg LH, Sisodia SS. Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm. Nature. 1997 May 15;387(6630):288-92
6. Selkoe DJ. Notch and presenilins in vertebrates and invertebrates: implications for neuronal development and degeneration. Curr Opin Neurobiol. 2000 Feb; 10(1):50-7.
7. De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature. 1998 Jan 22; 391(6665):387-90.
8. Takasugi N, Tomita T, Hayashi I, Tsuruoka M, Niimura M, Takahashi Y, Thinakaran G, Iwatsubo T. The role of presenilin cofactors in the gamma-secretase complex. Nature. 2003 Mar 27; 422(6930):438-41.
9. Vaucher E, Fluit P, Chishti MA, Westaway D, Mount HT, Kar S Object recognition memory and cholinergic parameters in mice expressing human presenilin 1 transgenes. Exp Neurol. 2002 Jun; 175(2):398-406.
10. Huang XG, Yee BK, Nag S, Chan ST, Tang F. Behavioral and neurochemical characterization of transgenic mice carrying the human presenilin-1 gene with orwithout the leucine-to-proline mutation at codon 235. Exp Neurol. 2003 Oct; 183(2):673-81.
11. Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T, Prada CM, Kim G, Seekins S, Yager D, Slunt HH, Wang R, Seeger M,Levey AI, Gandy SE, Copeland NG, Jenkins NA, Price DL, Younkin SG, Sisodia SS Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron. 1996 Nov; 17(5):1005-13.
12. Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-tur J, Hutton M, Buee L, Harigaya Y, Yager D,Morgan D, Gordon MN, Holcomb L, Refolo L, Zenk B, Hardy J, Younkin S. Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature. 1996 Oct 24; 383(6602):710-3.
13. Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, Johnson-Wood K, Lee M, Seubert P, Davis A, Kholodenko D, Motter R, Sherrington R, Perry B, Yao H, Strome R, Lieberburg I, Rommens J, Kim S, Schenk D, Fraser P, St George Hyslop P, Selkoe DJ. Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nat Med. 1997 Jan; 3(1):67-72.
14. Myers-Payne SC, Fontaine RN, Loeffler A, Pu L, Rao AM, Kier AB, Wood WG, Schroeder F Effects of chronic ethanol consumption on sterol transfer proteins in mouse brain. J Neurochem. 1996 Jan; 66(1):313-20.
15. Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J, Hutton M, Kukull W, Larson E, Levy-Lahad E, Viitanen M, Peskind E, Poorkaj P, Schellenberg G, Tanzi R, Wasco W, Lannfelt L, Selkoe D, Younkin S. Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat Med. 1996 Aug; 2(8):864-70.
16. Nakano Y, Kondoh G, Kudo T, Imaizumi K, Kato M, Miyazaki JI, Tohyama M, Takeda J, Takeda M. Accumulation of murine amyloidbeta42 in a gene-dosage-dependent manner in PS1 'knock-in' mice. Eur J Neurosci. 1999 Jul; 11(7):2577-81.
17. Chui DH, Tanahashi H, Ozawa K, Ikeda S, Checler F, Ueda O, Suzuki H, Araki W, Inoue H, Shirotani K, Takahashi K, Gallyas F, Tabira T. Transgenic mice withAlzheimer presenilin 1 mutations show accelerated neurodegeneration without amyloid plaque formation. Nat Med. 1999 May; 5(5):560-4.
18. Pigino G, Pelsman A, Mori H, Busciglio J. Presenilin-1 mutations reduce cytoskeletal association, deregulate neurite growth, and potentiate neuronal dystrophy and tau phosphorylation. J Neurosci. 2001 Feb 1; 21(3):834-42.
19. Gomez-Isla T, Wasco W, Pettingell WP, Gurubhagavatula S, Schmidt SD, Jondro PD, McNamara M, Rodes LA, DiBlasi T, Growdon WB, Seubert P, Schenk D, Growdon JH, Hyman BT, Tanzi RE. A novel presenilin-1 mutation: increased beta-amyloid and neurofibrillary changes. Ann Neurol. 1997 Jun; 41(6):809-13.
20. Guo Q, Sebastian L, Sopher BL, Miller MW, Ware CB, Martin GM, Mattson MP. Increased vulnerability of hippocampal neurons from presenilin-1 mutant knock-in mice to amyloid beta-peptide toxicity: central roles of superoxide production and caspase activity. J Neurochem. 1999 Mar; 72(3):1019-29.
21. Guo Q, Sopher BL, Furukawa K, Pham DG, Robinson N, Martin GM, Mattson MP. Alzheimer's presenilin mutation sensitizes neural cells to apoptosis induced by trophic factor withdrawal and amyloid beta-peptide: involvement of calcium and oxyradicals. J Neurosci. 1997 Jun 1; 17(11):4212-22.
22. Yankner BA, Duffy LK, Kirschner DA. Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science. 1990 Oct 12; 250(4978):279-82.
23. Behl C, Davis J, Cole GM, Schubert D. Vitamin E protects nerve cells from amyloid beta protein toxicity. Biochem Biophys Res Commun. 1992 Jul 31; 186(2):944-50.
24. Behl C, Davis JB, Lesley R, Schubert D. Hydrogen peroxide mediates amyloid beta protein toxicity. Cell. 1994 Jun 17; 77(6):817-27.
25. Butterfield DA, Hensley K, Harris M, Mattson M, Carney J. beta-Amyloid peptide free radical fragments initiate synaptosomal lipoperoxidation in a sequence-specific fashion: implications to Alzheimer's disease. Biochem Biophys Res Commun. 1994 Apr 29; 200(2):710-5.
26. Schubert D, Behl C, Lesley R, Brack A, Dargusch R, Sagara Y, Kimura H. Amyloid peptides are toxic via a common oxidative mechanism. Proc Natl Acad SciU S A. 1995 Mar 14; 92(6):1989-93.
27. Yankner BA. Mechanisms of neuronal degeneration in Alzheimer's disease. Neuron. 1996 May; 16(5):921-32.
28. Markesbery WR. Oxidative stress hypothesis in Alzheimer's disease. Free Radic Biol Med. 1997; 23(1):134-47.
29. Subbarao KV, Richardson JS, Ang LC Autopsy samples of Alzheimer's cortex show increased peroxidation in vitro. J Neurochem. 1990 Jul; 55(1):342-5.
30. Smith CD, Carney JM, Starke-Reed PE, Oliver CN, Stadtman ER, Floyd RA, Markesbery WR. Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease. Proc Natl Acad Sci U S A. 1991 Dec 1; 88(23):10540-3.
31. Mecocci P, MacGarvey U, Beal MF. Oxidative damage to mitochondrial DNA is increased in Alzheimer's disease. Ann Neurol. 1994 Nov; 36(5):747-51.
32. Mattson MP, Goodman Y Different amyloidogenic peptides share a similar mechanism of neurotoxicity involving reactive oxygen species and calcium. Brain Res. 1995 Apr 3; 676(1):219-24.
33. Mwangi S, Anitha M, Fu H, Sitaraman SV, Srinivasan S. Glial cell line-derived neurotrophic factor-mediated enteric neuronal survival involves glycogen synthase kinase-3beta phosphorylation and coupling with 14-3-3. Neuroscience. 2006 Nov 17; 143(1):241-51.
34. Anitha M, Chandrasekharan B, Salgado JR, Grouzmann E,Mwangi S, Sitaraman SV, Srinivasan S. Glial-derived neurotrophic factor modulates enteric neuronal survival and proliferation through neuropeptide Y. Gastroenterology. 2006 Oct; 131(4):1164-78.
35. Zachary I. Neuroprotective role of vascular endothelial growth factor: signalling mechanisms, biological function, and therapeutic potential. Neurosignals. 2005; 14(5):207-21.
36. Kretz A, Schmeer C, Tausch S, Isenmann S. Simvastatin promotes heat shock protein 27 expression and Akt activation in the rat retina and protects axotomized retinal ganglion cells in vivo. Neurobiol Dis. 2006 Feb; 21(2):421-30.
37. Noble W, Planel E, Zehr C, Olm V, Meyerson J, Suleman F, Gaynor K, Wang L,LaFrancois J, Feinstein B, Burns M, Krishnamurthy P, Wen Y, Bhat R, Lewis J, Dickson D, Duff K. Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci U S A. 2005 May 10; 102(19):6990-5.
38. Roberts MS, Woods AJ, Dale TC, Van Der Sluijs P, Norman JC. Protein kinase B/Akt acts via glycogen synthase kinase 3 to regulate recycling of alpha v beta 3 and alpha 5 beta 1 integrins. Mol Cell Biol. 2004 Feb; 24(4):1505-15.
39. Chan PH. Mitochondrial dysfunction and oxidative stress as determinants of cell death/survival in stroke. Ann N Y Acad Sci. 2005 May;1042:203-9.
40. Chong ZZ, Li F, Maiese K. Oxidative stress in the brain: novel cellular targets that govern survival during neurodegenerative disease. Prog Neurobiol. 2005 Feb; 75(3):207-46.
41. Taylor JM, Ali U, Iannello RC, Hertzog P, Crack PJ. Diminished Akt phosphorylation in neurons lacking glutathione peroxidase-1 (Gpx1) leads to increased susceptibility to oxidative stress-induced cell death. J Neurochem. 2005 Jan; 92(2):283-93.
42. Xia CF, Yin H, Borlongan CV, Chao J, Chao L. Adrenomedullin gene delivery protects against cerebral ischemic injury by promoting astrocyte migration and survival. Hum Gene Ther. 2004 Dec; 15(12):1243-54 .
43. Ernster L, Dallner G. Biochemical, physiological and medical aspects of ubiquinone function. Biochim Biophys Acta. 1995 May 24; 1271(1):195-204
44. Noack H, Kube U, Augustin W. Relations between tocopherol depletion and coenzyme Q during lipid peroxidation in rat liver mitochondria. Free Radic Res. 1994 Jun; 20(6):375-86.
45. Forsmark-Andree P, Lee CP, Dallner G, Ernster L. Lipid peroxidation and changes in the ubiquinone content and the respiratory chain enzymes of submitochondrial particles. Free Radic Biol Med. 1997; 22(3):391-400.
46. Beyer RE. An analysis of the role of coenzyme Q in free radical generation and as an antioxidant. Biochem Cell Biol. 1992 Jun; 70(6):390-403.
47. Modi K, Santani DD, Goyal RK, Bhatt PA. Effect of coenzyme Q10 on catalase activity and other antioxidant parameters in streptozotocin-induced diabetic rats.Biol Trace Elem Res. 2006 Jan; 109(1):25-34.
48. Marubayashi S, Dohi K, Ochi K, Kawasaki T. Protective effects of free radical scavenger and antioxidant administration on ischemic liver cell injury. Transplant Proc. 1987 Feb; 19(1 Pt 2):1327-8.
49. Matthews RT, Yang L, Browne S, Baik M, Beal MF. Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects. Proc Natl Acad Sci U S A. 1998 Jul 21; 95(15):8892-7.
50. Kamzalov S, Sumien N, Forster MJ, Sohal RS. Coenzyme Q intake elevates the mitochondrial and tissue levels of Coenzyme Q and alpha-tocopherol in young mice. J Nutr. 2003 Oct; 133(10):3175-80.
51. Shults CW, Oakes D, Kieburtz K, Beal MF, Haas R, Plumb S, Juncos JL, Nutt J, Shoulson I, Carter J, Kompoliti K, Perlmutter JS, Reich S, Stern M, Watts RL, Kurlan R, Molho E, Harrison M, Lew M; Parkinson Study Group. Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol. 2002 Oct; 59(10):1541-50.
52. Ferrante RJ, Andreassen OA, Dedeoglu A, Ferrante KL, Jenkins BG, Hersch SM, Beal MF. Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington's disease. J Neurosci. 2002 Mar 1; 22(5):1592-9.
53. Smith KM, Matson S, Matson WR, Cormier K, Del Signore SJ, Hagerty SW, Stack EC, Ryu H, Ferrante RJ. Dose ranging and efficacy study of high-dose coenzyme Q10 formulations in Huntington's disease mice. chim Biophys Acta. 2006 Jun; 1762(6):616-26
54. Traynor BJ, Bruijn L, Conwit R, Beal F, O'Neill G, Fagan SC, Cudkowicz ME. Neuroprotective agents for clinical trials in ALS: a systematic assessment. Neurology. 2006 Jul 11; 67(1):20-7.
55. Wu SS, Frucht SJ. Treatment of Parkinson's disease : what's on the horizon? CNS Drugs. 2005; 19(9):723-43.
56. Beal MF, Henshaw DR, Jenkins BG, Rosen BR, Schulz JB. Coenzyme Q10 and nicotinamide block striatal lesions produced by the mitochondrial toxin malonate. Ann Neurol. 1994 Dec; 36(6):882-8.
57. Koroshetz WJ, Jenkins BG, Rosen BR, Beal MF. Energy metabolism defects inHuntington's disease and effects of coenzyme Q10. Ann Neurol. 1997 Feb; 41(2):160-5.
58. McCarthy S, Somayajulu M, Sikorska M, Borowy-Borowski H, Pandey S.Paraquat induces oxidative stress and neuronal cell death; neuroprotection by water-soluble Coenzyme Q10. Toxicol Appl Pharmacol. 2004 Nov 15; 201(1):21-31.
59. Moreira PI, Santos MS, Sena C, Nunes E, Seica R, Oliveira CR. CoQ10 therapy attenuates amyloid beta-peptide toxicity in brain mitochondria isolated from aged diabetic rats. Exp Neurol. 2005 Nov; 196(1):112-9.
60. Ono K, Hasegawa K, Naiki H, Yamada M. Preformed beta-amyloid fibrils are destabilized by coenzyme Q10 in vitro. Biochem Biophys Res Commun. 2005 Apr 29; 330(1):111-6.
61. Li G, Zou L, Jack CR Jr, Yang Y, Yang ES. Neuroprotective effect of Coenzyme Q10 on ischemic hemisphere in aged mice with mutations in the amyloid precursor protein. Neurobiol Aging. 2006 Jun 26.
62. Grieb P, Ryba MS, Sawicki J, Chrapusta SJ. Oral coenzyme Q10 administration prevents the development of ischemic brain lesions in a rabbit model of symptomatic vasospasm. Acta Neuropathol (Berl). 1997 Oct; 94(4):363-8.
63. Ostrowski RP. Effect of coenzyme Q10 (CoQ10) on superoxide dismutase activity in ET-1 and ET-3 experimental models of cerebral ischemia in the rat. Folia Neuropathol. 1999; 37(4):247-51.
64. Tsukahara Y, Wakatsuki A, Okatani Y. Antioxidant role of endogenous coenzyme Q against the ischemia and reperfusion-induced lipid peroxidation in fetal rat brain. Acta Obstet Gynecol Scand. 1999 Sep; 78(8):669-74.
65. Campion D, Brice A, Dumanchin C, Puel M, Baulac M, De La Sayette V, Hannequin D, Duyckaerts C, Michon A, Martin C, Moreau V, Penet C, Martinez M, Clerget-Darpoux F, Agid Y, Frebourg T. A novel presenilin 1 mutation resulting in familial Alzheimer's disease with an onset age of 29 years. Neuroreport. 1996 Jul 8; 7(10):1582-4.
66. Rogaeva EA, Fafel KC, Song YQ, Medeiros H, Sato C, Liang Y, Richard E, Rogaev EI, Frommelt P, Sadovnick AD, Meschino W, Rockwood K, Boss MA, Mayeux R, St George-Hyslop P. Screening for PS1 mutations in a referral-basedseries of AD cases: 21 novel mutations. Neurology. 2001 Aug 28; 57(4):621-5.
67. Butterfield DA. Amyloid beta-peptide (1-42)-induced oxidative stress and neurotoxicity: implications for neurodegeneration in Alzheimer's disease brain. A review. Free Radic Res. 2002 Dec; 36(12):1307-13.
68. Boyd-Kimball D, Sultana R, Mohmmad-Abdul H, Butterfield DA. Rodent Abeta(1-
42) exhibits oxidative stress properties similar to those of human Abeta(1-42): Implications for proposed mechanisms of toxicity. Alzheimers Dis. 2004 Oct; 6(5):515-25.
69. Mohmmad Abdul H, Sultana R, Keller JN, St Clair DK, Markesbery WR, Butterfield DA. Mutations in amyloid precursor protein and presenilin-1 genes increase the basal oxidative stress in murine neuronal cells and lead to increased sensitivity to oxidative stress mediated by amyloid beta-peptide (1-42), HO and kainic acid: implications for Alzheimer's disease. J Neurochem. 2006 Mar; 96(5):1322-35.
70. Tamagno E, Parola M, Bardini P, Piccini A, Borghi R, Guglielmotto M, Santoro G, Davit A, Danni O, Smith MA, Perry G, Tabaton M. Beta-site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress-activated protein kinases pathways. Neurochem. 2005 Feb; 92(3):628-36.
71. Tong Y, Zhou W, Fung V, Christensen MA, Qing H, Sun X, Song W. Oxidative stress potentiates BACE1 gene expression and Abeta generation. J Neural Transm. 2005 Mar; 112(3):455-69.
72. Wang ZF, Li HL, Li XC, Zhang Q, Tian Q, Wang Q, Xu H, Wang JZ. Effects of endogenous beta-amyloid overproduction on tau phosphorylation in cell culture. J Neurochem. 2006 Aug; 98(4):1167-75.
73. Chong ZZ, Li F, Maiese K. Group I metabotropic receptor neuroprotection requires Akt and its substrates that govern FOXO3a, Bim, and beta-catenin during oxidative stress. Curr Neurovasc Res. 2006 May; 3(2):107-17.
74. Koh SH, Jung B, Song CW, Kim Y, Kim YS, Kim SH. 15-Deoxy-delta12,14-prostaglandin J2, a neuroprotectant or a neurotoxicant? Toxicology. 2005 Dec 15; 216(2-3):232-43.
75. Kilic U, Kilic E, Reiter RJ, Bassetti CL, Hermann DM. Signal transductionpathways involved in melatonin-induced neuroprotection after focal cerebral ischemia in mice. J Pineal Res. 2005 Jan; 38(1):67-71.
76. Li G, Zou LY, Cao CM, Yang ES. Coenzyme Q10 protects SHSY5Y neuronal cells from beta amyloid toxicity and oxygen-glucose deprivation by inhibiting the opening of the mitochondrial permeability transition pore. Biofactors. 2005; 25(1-4):97-107.
1. Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology. 1992 Mar; 42(3 Pt 1):631-9.
2. Feany MB, Dickson DW. Neurodegenerative disorders with extensive tau pathology: a comparative study and review. Ann Neurol. 1996 Aug; 40(2):139-48.
3. Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, Wisniewski HM. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem. 1986 May 5; 261(13):6084-9.
4. Lee VM, Balin BJ, Otvos L Jr, Trojanowski JQ. A68: a major subunit of paired helical filaments and derivatized forms of normal Tau. Science.1991 Feb 8; 251(4994):675-8.
5. Goedert M, Spillantini MG, Cairns NJ, Crowther RA. Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron. 1992 Jan; 8(1):159-68.
6. Kanemaru K, Takio K, Miura R, Titani K, Ihara Y. Fetal-type phosphorylation of the tau in paired helical filaments J Neurochem. 1992 May; 58(5):1667-75.
7. Sternberger NH, Sternberger LA, Ulrich J. Aberrant neurofilament phosphorylation in Alzheimer disease Proc Natl Acad Sci U S A. 1985 Jun;82(12):4274-6.
8. Wang J, Tung YC, Wang Y, Li XT, Iqbal K, Grundke-Iqbal I. Hyperphosphorylation and accumulation of neurofilament proteins in Alzheimer disease brain and in okadaic acid-treated SY5Y cells. FEBS Lett. 2001 Oct 19; 507(1):81-7.
9. Hu YY, He SS, Wang XC, Duan QH, Khatoon S, Iqbal K, Grundke-Iqbal I, Wang JZ. Elevated levels of phosphorylated neurofilament proteins in cerebrospinal fluid of Alzheimer disease patients. Neurosci Lett. 2002 Mar 8; 320(3):156-60.
10. Tian Q, Wang J. Role of serine/threonine protein phosphatase in Alzheimer's disease. Neurosignals. 2002 Sep-Oct; 11(5):262-9.
11. He J, Yamada K, Zou LB, Nabeshima T. Spatial memory deficit and neurodegeneration induced by the direct injection of okadaic acid into the hippocampus in rats. J Neural Transm. 2001; 108(12):1435-43.
12. Sun L, Liu SY, Zhou XW, Wang XC, Liu R, Wang Q, Wang JZ. Inhibition of protein phosphatase 2A- and protein phosphatase 1-induced tau hyperphosphorylation and impairment of spatial memory retention in rats. Neuroscience. 2003; 118(4):1175-82.
13. Arendt T, Holzer M, Fruth R, Bruckner MK, Gartner U. Paired helical filament-like phosphorylation of tau, deposition of beta/A4-amyloid and memory impairment in rat induced by chronic inhibition of phosphatase 1 and 2A. Neuroscience. 1995 Dec; 69(3):691-8.
14. Sanchez MP, Alvarez-Tallada V, Avila J. The microtubule-associated protein tau in neurodegenerative diseases. Tauopathies. Rev Neurol. 2001 Jul 16-31; 33(2):169-77.
15. Sang H, Lu Z, Li Y, Ru B, Wang W, Chen J. Phosphorylation of tau by glycogen synthase kinase 3beta in intact mammalian cells influences the stability of microtubules. Neurosci Lett. 2001 Oct 26; 312(3):141-4.
16. Lee MK, Cleveland DW. Neuronal intermediate filaments. Annu Rev Neurosci. 1996; 19:187-217.
17. de Waegh SM, Lee VM, Brady ST. Local modulation of neurofilament phosphorylation, axonal caliber, and slow axonal transport by myelinating Schwann cells. Cell. 1992 Feb 7; 68(3):451-63.
18. Shea TB, Paskevich PA, Beermann ML. The protein phosphatase inhibitor okadaic acid increases axonal neurofilaments and neurite caliber, and decreases axonal microtubules in NB2a/d1 cells. J Neurosci Res. 1993 Aug 1; 35(5):507-21.
19. Hoffman PN, Thompson GW, Griffin JW, Price DL. Changes in neurofilament transport coincide temporally with alterations in the caliber of axons in regenerating motor fibers. J Cell Biol. 1985 Oct; 101(4):1332-40.
20. Mudher A, Shepherd D, Newman TA, Mildren P, Jukes JP, Squire A, Mears A, Drummond JA, Berg S, MacKay D, Asuni AA, Bhat R, Lovestone S. GSK-3beta inhibition reverses axonal transport defects and behavioural phenotypes in Drosophila. Mol Psychiatry. 2004 May; 9(5):522-30.
21. Brzezinski A. Melatonin in humans. N Engl J Med. 1997 Jan 16; 336(3):186-95.
22. Wang DL, Ling ZQ, Cao FY, Zhu LQ, Wang JZ. Melatonin attenuates isoproterenol-induced protein kinase A overactivation and tau hyperphosphorylation in rat brain. J Pineal Res. 2004 Aug; 37(1):11-6.
23. Wang YP, Li XT, Liu SJ, Zhou XW, Wang XC, Wang JZ. Melatonin ameliorated okadaic-acid induced Alzheimer-like lesions. Acta Pharmacol Sin. 2004 Mar; 25(3):276-80.
24. Liu SJ, Wang JZ. Alzheimer-like tau phosphorylation induced by wortmannin in vivo and its attenuation by melatonin. Acta Pharmacol Sin. 2002 Feb; 23(2):183-7.
25. Li SP, Deng YQ, Wang XC, Wang YP, Wang JZ. Melatonin protects SH-SY5Y neuroblastoma cells from calyculin A-induced neurofilament impairment and neurotoxicity. J Pineal Res. 2004 Apr; 36(3):186-91.
26. Wang JZ, Wang ZF. Role of melatonin in Alzheimer-like neurodegeneration. Acta Pharmacol Sin. 2006 Jan; 27(1):41-9.
27. Paxinos G, Watson C, Pennisi M, Topple A. Bregma, lambda and the interaural midpoint in stereotaxic surgery with rats of different sex, strain and weight. J Neurosci Methods. 1985 Apr; 13(2):139-43.
28. Bourtchuladze R, Frenguelli B, Blendy J,Cioffi D, Schutz G, Silva AJ. Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell. 1994 Oct 7; 79(1):59-68.
29. Guzowski JF, McGaugh JL. Antisense oligodeoxynucleotide-mediated disruption of hippocampal cAMP response element binding protein levels impairs consolidation of memory for water maze training. Proc Natl Acad Sci U S A. 1997 Mar 18; 94(6):2693-8.
30. Gong CX, Singh TJ, Grundke-Iqbal I, Iqbal K. Phosphoprotein phosphatase activities in Alzheimer disease brain. J Neurochem. 1993 Sep; 61(3):921-7.
31. Sontag E, Nunbhakdi-Craig V, Lee G, Brandt R, Kamibayashi C, Kuret J, White CL 3rd, Mumby MC, Bloom GS. Molecular interactions among protein phosphatase 2A, tau, and microtubules. Implications for the regulation of tau phosphorylation and the development of tauopathies. J Biol Chem. 1999 Sep 3; 274(36):25490-8.
32. Wang JZ, Grundke-Iqbal I, Iqbal K. Restoration of biological activity of Alzheimer abnormally phosphorylated tau by dephosphorylation with protein phosphatase-2A, -2B and -1. Brain Res Mol Brain Res. 1996 Jun; 38(2):200-8.
33. Yamamoto T, Yuyama K, Nakamura K, Kato T, Yamamoto H. Kinetic characterization of the nitric oxide toxicity for PC12 cells: effect of half-life time of NO release. Eur J Pharmacol. 2000 May 26; 397(1):25-33.
34. Wang JZ, Gong CX, Zaidi T, Grundke-Iqbal I, Iqbal K. Dephosphorylation of Alzheimer paired helical filaments by protein phosphatase-2A and -2B. J Biol Chem. 1995 Mar 3; 270(9):4854-60.
35. Liu F, Grundke-Iqbal I, Iqbal K, Gong CX. Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation. Eur J Neurosci. 2005 Oct; 22(8):1942-50.
36. Tanaka T, Zhong J, Iqbal K, Trenkner E, Grundke-Iqbal I. The regulation of phosphorylation of tau in SY5Y neuroblastoma cells: the role of protein phosphatases. FEBS Lett. 1998 Apr 17; 426(2):248-54 .
37. Gong CX, Lidsky T, Wegiel J, Zuck L, Grundke-Iqbal I, Iqbal K. Phosphorylation of microtubule-associated protein tau is regulated by protein phosphatase 2A in mammalian brain. Implications for neurofibrillary degeneration in Alzheimer's disease. J Biol Chem. 2000 Feb 25; 275(8):5535-44.
38. Cash AD, Aliev G, Siedlak SL, Nunomura A, Fujioka H, Zhu X, Raina AK, Vinters HV, Tabaton M, Johnson AB, Paula-Barbosa M, Avila J, Jones PK, Castellani RJ, Smith MA, Perry G. Microtubule reduction in Alzheimer's disease and aging is independent of tau filament formation. Am J Pathol. 2003 May; 162(5):1623-7.
39. Stokin GB, Lillo C, Falzone TL, Brusch RG, Rockenstein E, Mount SL, Raman R, Davies P,Masliah E, Williams DS, Goldstein LS. Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease. Science. 2005 Feb 25; 307(5713):1282-8.
40. Smith DH, Chen XH, Iwata A, Graham DI. Amyloid beta accumulation in axons after traumatic brain injury in humans. J Neurosurg. 2003 May; 98(5):1072-7.
41. Yagishita S. Morphological investigations on axonal swellings and spheroids in various human diseases. Virchows Arch A Pathol Anat Histol. 1978 Jun 15; 378(3):181-97.
42. Biernat J, Gustke N, Drewes G, Mandelkow EM, Mandelkow E. Phosphorylation of Ser262 strongly reduces binding of tau to microtubules: distinction between PHF-like immunoreactivity and microtubule binding. Neuron. 1993 Jul; 11(1):153-63.
43. Davies CA, Mann DM, Sumpter PQ, Yates PO. A quantitative morphometric analysis of the neuronal and synaptic content of the frontal and temporal cortex in patients with Alzheimer's disease. J Neurol Sci. 1987 Apr; 78(2):151-64.
44. DeKosky ST, Scheff SW. Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann Neurol. 1990 May; 27(5):457-64.
45. Hall GF, Yao J. Neuronal morphology, axonal integrity, and axonal regeneration in situ are regulated by cytoskeletal phosphorylation in identified lamprey central neurons. Microsc Res Tech. 2000 Jan 1; 48(1):32-46.
46. Jung C, Yabe JT, Lee S, Shea TB. Hypophosphorylated neurofilament subunits undergo axonal transport more rapidly than more extensively phosphorylated subunits in situ. Cell Motil Cytoskeleton. 2000 Oct; 47(2):120-9.
47. Hirokawa N, Takeda S. Gene targeting studies begin to reveal the function of neurofilament proteins. J Cell Biol. 1998 Oct 5; 143(1):1-4.
48. Hoffman PN, Griffin JW, Price DL. Control of axonal caliber by neurofilament transport. J Cell Biol. 1984 Aug; 99(2):705-14.
49. Ren QG, Liao XM, Wang ZF, Qu ZS, Wang JZ. The involvement of glycogen synthase kinase-3 and protein phosphatase-2A in lactacystin-induced tau accumulation. FEBS Lett. 2006 May 1; 580(10):2503-11.
1. Dallner G, Stocker R, Coenzyme Q. In: Encyclopedia of dietary supplements. New York: Marcel Dekker; 2005. pp. 121–131. A comprehensive yet synthetic review highlighting both the biochemical aspects and clinical implications of coenzyme Q.
2. Groneberg DA, Kindermann B, Althammer M, et al. Coenzyme Q10 affects expression of genes involved in cell signalling, metabolism and transport in human CaCo-2 cells. Int J Biochem Cell Biol 2005; 37:1208–1218. The findings of this paper are innovative and represent the first demonstration that CoQ10 affects gene expression in vitro.
3. M. Flint Beal. Therapeutic Effects of Coenzyme Q10 in Neurodegenerative Diseases. METHODS IN ENZYMOLOGY 2004; 382: 473-487.
4. Crane FL, Hatefi Y, Lester RL, Widmer C (1957) Isolation of a quinone from beef heart mitochondria. Biochim Biophys Acta 25:220–221.
5. Kuglstatter A, Miksovska J, Sebban P, Fritzsch G. Structure of the photosynthetic reaction centre from Rhodobacter sphaeroides reconstituted with anthraquinone as primary quinone Q(A). FEBS Lett. 2000 Apr 21; 472(1):114-116.
6. Lenaz G (ed):“Coenzyme Q.”Chichester: Wiley, 1985.
7. McAuley KE, Fyfe PK, Ridge JP, Cogdell RJ, Isaacs NW, Jones MR. Ubiquinone binding, ubiquinone exclusion, and detailed cofactor conformation in a mutant bacterial reaction center. Biochemistry. 2000 Dec 12; 39(49):15032-43.
8. Schmid R, Gerloff DL.Functional properties of the alternative NADH:ubiquinone oxidoreductase from E. coli through comparative 3-D modelling. FEBS Lett. 2004 Dec 3; 578(1-2):163-8.
9. Kalen A, Norling B, Appelkvist EL, Dallner G: Ubiquinone biosynthesis by the microsomal fraction of rat liver. Biochim Biophys Acta 926:70–78, 1987.
10. Cramer WA, Soriano GM: Energy transduction function of the quinone reactions in cytochrome bc complexes. Biofactors 9:81–86, 1999.
11. Brandt U: Proton translocation in the respiratory chain involving ubiquinone—a hypothetical semiquinone switch mechanism for complex I. Biofactors 9:95–102, 1999.
12. Yu CA, Zhang K-P, Deng H, Xia D, Klm H, Deisenhofer J, Yu L: Structure and reaction mechanisms of the multifunctional mitochondrial cytochrome bc1 complex. Biofactors 9:103–110, 1999.
13. Takahashi T, Okamoto T, Mori K, Sayo H, Kishi T: Distribution of ubiquinone and ubiquinol homologues in rat tissues and subcellular fraction. Lipids 28:803–809, 1993.
14. Quinn PJ, Fabisiak JP, Kagan VE: Expansion of the antioxidant function of vitamin E by coenzyme Q. Biofactors 9:149–154, 1999.
15. Takahashi T, Okamoto T, Kishi T: Characterization of NADPH dependent ubiquinone reductase activity in rat liver cytosol. J Biochem 119:256–263, 1996.
16. Villalba JM, Navas P: Plasma membrane redox system in the control of stress induced apoptosis. Antioxid Redox Signal 2:213–230, 2000.
17. Crane FL: New functions for coenzyme Q. Protoplasma, 213:127–133, 2000.
18. Poon WW, Do TQ, Marbois BN, Clarke CF: Sensitivity to treatment with polyunsaturated fatty acids is a general characteristic of the ubiquinone-deficient yeast coq mutants. Mol Aspect Med 18(S):121–128, 1997.
19. McLennan H, Degli Esposti M: The contribution of mitochondrial respiratory complexes to the production of reactive oxygen species. J Bioenerg Biomemb 32:153–162, 2000.
20. Kaltschmidt B, Sparna T, Kaltschmidt C: Activation of NFKB by reactive oxygen intermediates in the nervous system. Antioxid Redox Signal 1:129–144, 1999.
21. Morad M, Suzuki YJ: Redox regulation of cardiac muscle calcium signaling. Antioxid Redox Signal 2:65–71, 2000.
22. Schipper HM. Brain iron deposition and the free radical-mitochondrial theory of ageing. Ageing Res Rev 2004; 3: 265-301.
23. Kidd PM. A review of nutrients and botanicals in the integrative management of cognitive dysfunction. Altern Med Rev 1999; 4: 144-161.
24. Gary EG, Hsueh-Meei H. Oxidative stress in Alzheimer’s disease. Neurobiol Aging 2005; 26:575–8.
25. Sullivan PG, Brown MR. Mitochondrial aging and dysfunction in Alzheimer’s disease. Progr Neuropsychopharmacol Biol Psychiatry 2005; 29: 407-410.
26. Gabuzda, D., Busciglio, J., Chen, L. B., Matsudaira, P., and Yankner, B. A. (1994). J. Biol. Chem. 269, 13623–13628.
27. Ohyagi, Y., Yamada, T., Nishioka, K., Clarke, N. J., Tomlinson, A. J., Naylor, S., Nakabeppu, Y., Kira, J., and Younkin, S. G. (2000). Neuroreport 11, 167–171.
28. Tamagno, E., Bardini, P., Obbili, A., Vitali, A., Borghi, R., Zaccheo, D.,Pronzato, M. A., Danni, O., Smith, M. A., Perry, G., and Tabaton, M. (2002). Neurobio. Dis. 10, 279–288.
29. Drake, J., Link, C. D., and Butterfield, D. A. (2003). Neurobiol. Aging 24, 415–420.
30. S?derberg, M.; Edlund, C.; Alafuzoff. I.; Kristensson, K.; Dallner,G. J. Neurochem., 1992, 59, 1646.
31. Barja G. Free radicals and aging. Trends Neurosci 2004; 27: 595-600.
32. K. S. Echtay, E. Winkler, and M. Klingenberg, Nature 408, 609 (2000).
33. K. Echtay, E. Winkler, K. Frischmuth, and M. Klingenberg, Proc. Natl. Acad. Sci. USA 98, 1416 (2001).
34. D. Ricquier and F. Bouillaud, Biochem. J. 345, 161 (2000).
35. P. G. Sullivan, C. Dube, K. Dorenbos, O. Steward, and T. Z. Baram, Ann. Neurol., published online (2003).
36. L. Walter, V. Nogueira, X. Leverve, M. P. Heitz, P. Bernardi, and E. Fontaine, J. Biol. Chem. 275, 29521 (2000).
37. E. Fontaine, F. Ichas, and P. Bernardi, J. Biol. Chem. 273, 25734 (1998).
38. Geng Li , Liangyu Zou, Clifford R. Jack Jr. ,Yihong Yang , Edward S. Yang. Neuroprotective effect of Coenzyme Q10 on ischemic hemisphere in aged mice with mutations in the amyloid precursor protein. Neurobiology of Aging 2006.
39. Matthews RT, Yang L, Browne S, Baik M, Beal MF. Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects. Proc Natl Acad Sci USA 1998; 95(15):8892–7.
40. Ostrowski RP. Effect of coenzyme Q (10) on biochemical and morphological changes in experimental ischemia in the rat brain. Brain Res Bull 2000; 53(4):399–407.
41. Tauheed Ishrat , M. Badruzzaman Khan, Md. Nasrul Hoda, Seema Yousuf et al. Coenzyme Q10 modulates cognitive impairment against intracerebroventricularinjection of streptozotocin in rats. Behav Brain Res. 2006; 171(1):9-16.
42. Beal MF. Mitochondrial dysfunction and oxidative damage in Alzheimer’s and Parkinson’s diseases and coenzyme Q10 as a potential treatment. J Bioenerg Biomembr 2004; 36:381–386.
43. Winkler-Stuck K, Widemann FR, Wallesch CW, Kunz WS. Effect of coenzyme Q10 on the mitochondrial function of skin fibroblasts from Parkinson patients. J Neurol Sci 2004; 220:41–48.
44. Janetzky, B., Hauck, S., Youdim, M. B., Riederer, P., Jellinger, K., Pantucek, F., Zochling, R., Boissl, K. W., Reichmann, H. (1994). Neurosci. Lett. 169, 126–128.
45. Betarbet, R., Sherer, T. B., MacKenzie, G., Garcia-Osuna, M., Panov, A. V., and Greenamyre, J. T. (2000). Nat. Neurosci. 3, 1301–1306.
46. Eriksen JL, Wszolek Z, Petrucelli L. Molecular pathogenesis of Parkinson disease. Arch Neurol 2005; 62:353-357.
47. Ikebe, S.-I., Tanaka, M., Ozawa, T., 1995. Point mutations of mitochondrial genome in Parkinson’s disease. Mol. Brain Res. 28, 281–295.
48. Gu, M., Cooper, J. M., Taanman, J. W., and Schapira, A. H. V. (1998). Ann. Neurol. 44, 177–186.
49. Kirchner, S.C., Hallagan, S.E., Farin, F.M., Dilley, J., Costa-Mallen, P., Smith-Weller, T., Franklin, G.M., Swanson, P.D., Checkoway, H., 2000. Mitochondrial ND1 sequence analysis and association of the T4216C mutation with Parkinson’s disease. Neurotoxicology 21 (4), 441–446.
50. Thyagarajan, D., Bressman, S., Bruno, C., Przedborski, S., Shanske, S., Lynch, T., Fahn, S., and DiMauro, S. (2000). Ann. Neurol. 48, 730–736.
51. Masashi Tanaka (2002). Mitochondrial genotypes and cytochrome b variants associated with longevity or Parkinson’s disease. J Neurol. 249 Suppl 2:II11-8/
52. Matsubara, T.; Azuma, T.; Yoshida, S.; Yamagami, T. In: Biomedical and clinical aspects of coenzyme Folkers, Q.K.; Littarru, G.P.; Yamagami, T. Eds. Elsevier Science Publishers, 1991, pp.159-166.
53. Molina, J.A.; de Bustos, F.; Ortiz, S.; Del Ser, T.; Seijo, M.; Benito-Léon, J.; Oliva, J.M.; Pérez, S.; Manzanares, J. Neural. Transm., 2002, 109, 1195.
54. Somayajulu M, McCarthy S, Hung M, et al. Role of mitochondria in neuronal celldeath induced by oxidative stress: neuroprotection by coenzyme Q10. Neurobiol Dis 2005; 18:618–627.
55. M. Flint Beal. Coenzyme Q10 administration and its potential for treatment of neurodegenerative diseases. BioFactors 1999; 9: 261–266.
56. Shults CW, Oakes D, Kieburtz K, et al. Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol 2002; 59:1541–1550.
57. Shults CW, Flint Beal M, Song D, Fontaine D. Pilot trial of high dosages of coenzyme Q10 in patients with Parkinson’s disease. Exp Neurol 2004; 188:491–494.
58. Gille G, Hung ST, Reichmann H, Rausch WD. Oxidative stress to dopaminergic neurons as models of Parkinson’s disease. Ann N Y Acad Sci 2004; 1018:533–540.
59. Sharma SK, El Refaey H, Ebadi M. Complex-1 activity and 18F-DOPA uptake in genetically engineered mouse model of Parkinson’s disease and the neuroprotective role of coenzyme Q10. Brain Res Bull. 2006 Jun 15; 70(1):22-32.
60. Sohmiya M, Tanaka M, Tak NW, et al. Redox status of plasma coenzyme Q10 indicates elevated systemic oxidative stress in Parkinson’s disease. J Neurol Sci 2004; 223:161–166.
61. Gardian G, Vecsei L. Huntington’s disease: pathomechanism and therapeutic perspectives. J Neural Transm 2004; 111: 1485-1494.
62. Goebel, H.H.; Heipertz, R.; Scholz, W.; Iqbal, K.; Tellez-Nagel, I. Neurology, 1978, 28, 23.
63. Brouillet, E.; Hantraye, P.; Ferrante, R.J.; Dolan, R.; Leroy-Willig, A.; Kowall, N.W.; Beal, M.F. Proc. Natl. Acad. Sci. USA, 1995, 92, 7105.
64. Tabrizi SJ, Workman J, Hart PE, et al. Mitochondrial dysfunction and free radical damage in the Huntington R6/2 transgenic mouse. Ann Neurol. 2000 Jan; 47(1):80-6.
65. Browne, S.E.; Bowling, A.C.; MacGarvey, U.; Baik, M.J.; Berger, S.C.; Muqit, M.M.; Bird, E.D.; Beal, M.F. Ann. Neurol., 1997, 41,646.
66. Gu, M.; Gash, M.T.; Mann, V.M.; Javoy-Agid, F.; Cooper, J.M.; Schapira, A.H. Ann. Neurol., 1996, 39, 385.
67. Koroshetz WJ, Jenkins BG, Rosen BR, Beal MF. Energy metabolism defects in Huntington’s disease and effects of coenzyme Q10. Ann Neurol 1997; 41:160-165.
68. Panov, A.V.; Gutekunst, C.A.; Leavitt, B.R.; Hayden, M.R.; Burke, J.R.; Strittmatter, W.J.; Greenamyre, J.T. Nat. Neurosci., 2002, 5,731.
69. Weydt P, Pineda VV, Torrence AE, et al.Thermoregulatory and metabolic defects in Huntington's disease transgenic mice implicate PGC-1alpha in Huntington's disease neurodegeneration. Cell Metab. 2006 Nov; 4(5):349-62.
70. Cui L, Jeong H, Borovecki F, Parkhurst CN, Tanese N, Krainc D. Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell. 2006 Oct 6; 127(1):59-69.
71. Beal, M.F.; Henshaw, D.R.; Jenkins, B.G.; Rosen, B.R.; Schulz, J.B. Ann. Neurol., 1994, 36, 882.
72. Ferrante RJ, Andreassen OA, Dedeoglu A, Ferrante KL, et al. Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington's disease. J Neurosci. 2002 Mar 1; 22(5):1592-9.
73. Andrich J, Saft C, Gerlach M. Coenzyme Q10 serum levels in Huntington's disease. J Neural Transm Suppl. 2004; (68):111-6.
74. Smith KM, Matson S, Matson WR, Cormier K et al. Dose ranging and efficacy study of high-dose coenzyme Q10 formulations in Huntington's disease mice. Biochim Biophys Acta. 2006 Jun; 1762(6):616-26.