Flavonoid-mediated presenilin-1 phosphorylation reduces Alzheimer's disease beta-amyloid production

Kavon Rezai-Zadeh, R Douglas Shytle, Yun Bai, Jun Tian, Huayan Hou, Takashi Mori, Jin Zeng, Demian Obregon, Terrence Town, Jun Tan, Kavon Rezai-Zadeh, R Douglas Shytle, Yun Bai, Jun Tian, Huayan Hou, Takashi Mori, Jin Zeng, Demian Obregon, Terrence Town, Jun Tan

Abstract

Glycogen synthase kinase 3 (GSK-3) dysregulation is implicated in the two Alzheimer's disease (AD) pathological hallmarks: beta-amyloid plaques and neurofibrillary tangles. GSK-3 inhibitors may abrogate AD pathology by inhibiting amyloidogenic gamma-secretase cleavage of amyloid precursor protein (APP). Here, we report that the citrus bioflavonoid luteolin reduces amyloid-beta (Abeta) peptide generation in both human 'Swedish' mutant APP transgene-bearing neuron-like cells and primary neurons. We also find that luteolin induces changes consistent with GSK-3 inhibition that (i) decrease amyloidogenic gamma-secretase APP processing, and (ii) promote presenilin-1 (PS1) carboxyl-terminal fragment (CTF) phosphorylation. Importantly, we find GSK-3alpha activity is essential for both PS1 CTF phosphorylation and PS1-APP interaction. As validation of these findings in vivo, we find that luteolin, when applied to the Tg2576 mouse model of AD, decreases soluble Abeta levels, reduces GSK-3 activity, and disrupts PS1-APP association. In addition, we find that Tg2576 mice treated with diosmin, a glycoside of a flavonoid structurally similar to luteolin, display significantly reduced Abeta pathology. We suggest that GSK-3 inhibition is a viable therapeutic approach for AD by impacting PS1 phosphorylation-dependent regulation of amyloidogenesis.

Figures

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Luteolin reduces Aβ generation and decreases γ-secretase cleavage activity in cultured neuronal cells. SweAPP N2a cells (A, B) or Tg2576 derived neuronal cells (C, D) were treated with luteolin at various concentrations as indicated for 12 hrs. For A, C, Secreted Aβ1–40, 42 peptides were analysed by immunoprecipitation/Western blot (right) and ELISA (left; n= 3 for each condition) in conditional media. For Aβ ELISA, data are represented as a percentage of Aβ1–40, 42 peptides secreted 12 hrs after luteolin treatment relative to control (untreated). (B, D) APP CTFs were analysed by Western blot (right) in cell lysates and relative fold mean over control (α, β-CTF) was calculated by Densitometry analysis (left). (A-D) One-way ANOVA followed by post hoc comparison revealed significant differences between each concentration (P < 0.005) except between 20 μM and 40 μM (P > 0.05). SweAPP N2a cells were treated with luteolin at a single concentration (20 μM) for various time-points as indicted. (E) Secreted Aβ1–40, 42 peptides were analysed in conditional media by ELISA following 12 hrs of incubation (top panel; n= 3 for each condition) and γ-secretase activity was analysed in cell lysates following 90 min. of incubation using secretase cleavage activity assay (lower panel; n= 3 for each condition). For (E), data presented as a percentage of fluorescence units/milligrams protein activated 30, 60, 90, 120, 300 min. after luteolin treatment relative to control (untreated). (E) A difference was noted between each time-point examined (P < 0.005). In parallel, we employed a similar structure compound, apigenin, as control. However, we did not observe similar results as luteolin (data not shown).
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Luteolin reduces Aβ generation and decreases γ-secretase cleavage activity in cultured neuronal cells. SweAPP N2a cells (A, B) or Tg2576 derived neuronal cells (C, D) were treated with luteolin at various concentrations as indicated for 12 hrs. For A, C, Secreted Aβ1–40, 42 peptides were analysed by immunoprecipitation/Western blot (right) and ELISA (left; n= 3 for each condition) in conditional media. For Aβ ELISA, data are represented as a percentage of Aβ1–40, 42 peptides secreted 12 hrs after luteolin treatment relative to control (untreated). (B, D) APP CTFs were analysed by Western blot (right) in cell lysates and relative fold mean over control (α, β-CTF) was calculated by Densitometry analysis (left). (A-D) One-way ANOVA followed by post hoc comparison revealed significant differences between each concentration (P < 0.005) except between 20 μM and 40 μM (P > 0.05). SweAPP N2a cells were treated with luteolin at a single concentration (20 μM) for various time-points as indicted. (E) Secreted Aβ1–40, 42 peptides were analysed in conditional media by ELISA following 12 hrs of incubation (top panel; n= 3 for each condition) and γ-secretase activity was analysed in cell lysates following 90 min. of incubation using secretase cleavage activity assay (lower panel; n= 3 for each condition). For (E), data presented as a percentage of fluorescence units/milligrams protein activated 30, 60, 90, 120, 300 min. after luteolin treatment relative to control (untreated). (E) A difference was noted between each time-point examined (P < 0.005). In parallel, we employed a similar structure compound, apigenin, as control. However, we did not observe similar results as luteolin (data not shown).
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Luteolin reduces GSK-3α activation. SweAPP N2a cells (A, B, C) or Tg2576-derived neuronal cells (D, E, F) were treated with luteolin at 20 μM for various time-points as indicated. Cell lysates were prepared and subjected to Western blot analysis in phosphorylated forms of GSK-3α/β. For (A, D), Western blot analysis using anti-phospho-GSK-3α (Ser21) antibody shows one band (51 kD) corresponding to phosphorylated form of GSK-3α or using anti-GSK-3 monoclonal antibody recognizes both total GSK-3α and GSK-3β, 51 and 47 kD, respectively. Western blot analysis using anti-actin antibody shows actin protein (as an internal reference control). Densitometry analysis shows the ratio of phospho-GSK-3α (Ser21) to total GSK-3α as indicated below the figures (n= 3 for each condition). (A, D) One-way ANOVA followed by post hoc comparison revealed a significant difference between 0 min. and 5, 10, 15, 20 or 25 min. (P < 0.001). For (B, E), Western blot analysis using anti-phospho-GSK-3α/β(Tye279/216) antibody shows two bands (51 and 47 kD) corresponding to phosphorylated forms of GSK-3α and GSK-3β or using anti-phospho-GSK-3β (Ser9) antibody recognizes phosphorylated form of GSK-3B at 47 kD. Anti-actin antibody was used as shows an internal reference control. Densitometry analysis shows the ratio of phospho-GSK-3α (Tye279/216) to total GSK-3α as indicated below the figures (n= 3 for each condition). (B, E) One-way ANOVA followed by post hoc comparison significant difference was noted between 30 min. and 45, 60, 75, 90, 120, 150 or 180 min. (P < 0.005). For (C, F), plots comparing ratios of phospho-GSK-3α (Ser21) and phospho-GSK-3α/β(Tye279/216) to total GSK-3α from densitometic analysis of Western blots over time.
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Luteolin reduces GSK-3α activation. SweAPP N2a cells (A, B, C) or Tg2576-derived neuronal cells (D, E, F) were treated with luteolin at 20 μM for various time-points as indicated. Cell lysates were prepared and subjected to Western blot analysis in phosphorylated forms of GSK-3α/β. For (A, D), Western blot analysis using anti-phospho-GSK-3α (Ser21) antibody shows one band (51 kD) corresponding to phosphorylated form of GSK-3α or using anti-GSK-3 monoclonal antibody recognizes both total GSK-3α and GSK-3β, 51 and 47 kD, respectively. Western blot analysis using anti-actin antibody shows actin protein (as an internal reference control). Densitometry analysis shows the ratio of phospho-GSK-3α (Ser21) to total GSK-3α as indicated below the figures (n= 3 for each condition). (A, D) One-way ANOVA followed by post hoc comparison revealed a significant difference between 0 min. and 5, 10, 15, 20 or 25 min. (P < 0.001). For (B, E), Western blot analysis using anti-phospho-GSK-3α/β(Tye279/216) antibody shows two bands (51 and 47 kD) corresponding to phosphorylated forms of GSK-3α and GSK-3β or using anti-phospho-GSK-3β (Ser9) antibody recognizes phosphorylated form of GSK-3B at 47 kD. Anti-actin antibody was used as shows an internal reference control. Densitometry analysis shows the ratio of phospho-GSK-3α (Tye279/216) to total GSK-3α as indicated below the figures (n= 3 for each condition). (B, E) One-way ANOVA followed by post hoc comparison significant difference was noted between 30 min. and 45, 60, 75, 90, 120, 150 or 180 min. (P < 0.005). For (C, F), plots comparing ratios of phospho-GSK-3α (Ser21) and phospho-GSK-3α/β(Tye279/216) to total GSK-3α from densitometic analysis of Western blots over time.
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PS1 phosphorylation is associated with luteolin-mediated inhibition of Aβ generation. SweAPP N2a cells were treated with luteolin at a range of concentrations for 4 hrs or at 20 μM for various time-points as indicated. Cell lysates were prepared from these cells and subjected to Western blot analyses of PS1 C-terminal fragments (CTF) (A) and N-terminal fragment (NTF) (C). Western blot analysis by anti-PS1 CTF antibody shows two bands corresponding to phosphorylated PS1 CTF (p-CTF) and one dephosphorylated PS1 CTF (CTF). While Western blot analysis by anti-PS1 CTF antibody shows tow bands corresponding to holo PS1 and PS1 NTF. For (B), cell lysates from luteolin treated cells (20 μM) were incubated with calf-intestine alkaline phosphatase (CIAP) or buffer for various time-points. Western blot analysis by anti-PS1 CTF antibody confirms two higher molecular weight bands corresponding to phosphorylated isoforms. Densitometry analysis shows the ratio of PS1 p-CTF to CTF below figures. A t-test revealed a significant deference between luteolin concentrations and time-points for ratio of PS1 p-CTF to CTF (P < 0.005 with n= 3 for each condition, but not for ratio of holo PS1 to PS1 NTF (P > 0.05 with n= 3 for each condition) at each time-point examined. Cultured media were collected for Aβ ELISA. Data correspond to percentage of Aβ1–40, 42 peptides secreted 4 hrs after luteolin treatment relative to control (untreated) as indicated below panel (A).
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GSK-3α regulates PS1 phosphorylation. For (A), SweAPP N2a cells were treated with a known GSK-3 inhibitor (SB-415286) at 20 μM for various time-points. Western blot analysis by anti-PS1 CTF antibody produces a similar phosphorylation profile to that of luteolin-treated cells. Densitometry analysis shows the ratio of PS1 p-CTF to CTF and ratio of holo PS1 to actin as indicated below the figures. A t-test revealed significant differences between time-points for the ratio of PS1 p-CTF to CTF (P < 0.001 with n= 3 for each condition). For (B), expression of PS1 C-terminal fragments was analysed by Western blot in cell lysates from SweAPP N2a cells transfected with siRNA targeting GSK-3α, β, or mock transfected 48 hrs after transfecion. Prior to experiments, siRNA knockdown efficiency >70% for GSK-3α, β was confirmed by Western blot analysis (data not shown). Densitometric analysis reveals the ratio of PS1 p-CTF to CTF as indicated below the each panel. A t-test revealed significant differences between GSK-3α siRNA-trans-fected cells and GSK-3β siRNA or control (Mock transfected cells) (P < 0.001 with n= 4 for each condition) on the ratio of PS1 p-CTF to CTF. In addition, a t-test also revealed significant differences between luteolin-treated cells and GSK-3β siRNA or control (Mock transfeced cells) (P < 0.001 with n= 4 for each condition) on the ratio of PS1 p-CTF to CTF.
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GSK-3α regulates PS1-APP association. SweAPP N2a cells were treated with either luteolin (20 μm) or SB-415286 (20 μm) for 4 hrs. Cell lysates from these treated cells and GSK-3α siRNA-transfected cells were subsequently analysed by immunoprecipitation/ Western blot. For (A), lysates were immunoprecipitated by anti-PS1 CTF antibody. Densitometric analysis of Western blot by 6E10 antibody shows the ratio of APP to IgG as indicated below panel (A). A t-test revealed significant differences between all treatments and control (P < 0.001 with n= 3 for each condition). For (B), cell lysates were analysed by Western blot by 6E10 antibody. Densitometric analysis of Western blot by anti-actin antibody reveals no significant changes in the ratio of APP to actin as indicated below panel (B) (P > 0.05).
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Luteolin reduces GSK-3 activation and cerebral amyloidosis in Tg2576 mice. Brain homogenates and sections from Tg2576 mice treated with luteolin (n= 5) or vehicle (PBS, n = 5). For (A), homogenates were analysed by Western blot with active and holo anti-GSK-3 antibodies with anti-actin antibodies as an internal control. Densitometric analysis reveals the ratio of active phosphorylated GSK-3α/β to holo GSK-3. A t-test reveals significant reductions in both active GSK-3α and β isoforms from luteolin-treated animals compared to control (P < 0.001). For (B), homogenates were analysed by Western blot with anti-PS1 CTF or NTF antibody. Densitometric analysis produces the ratio of PS1 CTF or NTF to actin (internal control). A t-test shows significant reductions in PS1 CTF levels with luteolin treatment (P <0.001), but not for PS1 NTF levels (P >0.05). For (C), immunochemistry staining analysis for active phosphorylated GSK-3α/β. For (D), homogenates were immunoprecipitated by anti-PS1 CTF antibody. Densitometric analysis of Western blot by 6E10 antibody shows the ratio of APP to IgG. A t-test revealed significant differences between luteolin treatment and control (P < 0.001). For (E), homogenates were analysed by Western blot by 6E10 antibody. Approximately 12-kD band may represent oligomeric form of amyloid. Densitometric analysis of Western blot by anti-actin antibody reveals no significant changes in the ratio of APP to actin. For (F), soluble and insoluble Aβ1–40, 42 peptides from homogenates were analysed by ELISA. For Aβ ELISA, data are represented as picograms of peptide present in milligrams of total protein. Luteolin treatment results in markedly reduced soluble Aβ1–40, 42 levels, 25% and 49%, respectively (top panel). No significant reductions in insoluble Aβ isoforms following treatment were observed (bottom panel).
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Luteolin reduces GSK-3 activation and cerebral amyloidosis in Tg2576 mice. Brain homogenates and sections from Tg2576 mice treated with luteolin (n= 5) or vehicle (PBS, n = 5). For (A), homogenates were analysed by Western blot with active and holo anti-GSK-3 antibodies with anti-actin antibodies as an internal control. Densitometric analysis reveals the ratio of active phosphorylated GSK-3α/β to holo GSK-3. A t-test reveals significant reductions in both active GSK-3α and β isoforms from luteolin-treated animals compared to control (P < 0.001). For (B), homogenates were analysed by Western blot with anti-PS1 CTF or NTF antibody. Densitometric analysis produces the ratio of PS1 CTF or NTF to actin (internal control). A t-test shows significant reductions in PS1 CTF levels with luteolin treatment (P <0.001), but not for PS1 NTF levels (P >0.05). For (C), immunochemistry staining analysis for active phosphorylated GSK-3α/β. For (D), homogenates were immunoprecipitated by anti-PS1 CTF antibody. Densitometric analysis of Western blot by 6E10 antibody shows the ratio of APP to IgG. A t-test revealed significant differences between luteolin treatment and control (P < 0.001). For (E), homogenates were analysed by Western blot by 6E10 antibody. Approximately 12-kD band may represent oligomeric form of amyloid. Densitometric analysis of Western blot by anti-actin antibody reveals no significant changes in the ratio of APP to actin. For (F), soluble and insoluble Aβ1–40, 42 peptides from homogenates were analysed by ELISA. For Aβ ELISA, data are represented as picograms of peptide present in milligrams of total protein. Luteolin treatment results in markedly reduced soluble Aβ1–40, 42 levels, 25% and 49%, respectively (top panel). No significant reductions in insoluble Aβ isoforms following treatment were observed (bottom panel).
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Luteolin reduces GSK-3 activation and cerebral amyloidosis in Tg2576 mice. Brain homogenates and sections from Tg2576 mice treated with luteolin (n= 5) or vehicle (PBS, n = 5). For (A), homogenates were analysed by Western blot with active and holo anti-GSK-3 antibodies with anti-actin antibodies as an internal control. Densitometric analysis reveals the ratio of active phosphorylated GSK-3α/β to holo GSK-3. A t-test reveals significant reductions in both active GSK-3α and β isoforms from luteolin-treated animals compared to control (P < 0.001). For (B), homogenates were analysed by Western blot with anti-PS1 CTF or NTF antibody. Densitometric analysis produces the ratio of PS1 CTF or NTF to actin (internal control). A t-test shows significant reductions in PS1 CTF levels with luteolin treatment (P <0.001), but not for PS1 NTF levels (P >0.05). For (C), immunochemistry staining analysis for active phosphorylated GSK-3α/β. For (D), homogenates were immunoprecipitated by anti-PS1 CTF antibody. Densitometric analysis of Western blot by 6E10 antibody shows the ratio of APP to IgG. A t-test revealed significant differences between luteolin treatment and control (P < 0.001). For (E), homogenates were analysed by Western blot by 6E10 antibody. Approximately 12-kD band may represent oligomeric form of amyloid. Densitometric analysis of Western blot by anti-actin antibody reveals no significant changes in the ratio of APP to actin. For (F), soluble and insoluble Aβ1–40, 42 peptides from homogenates were analysed by ELISA. For Aβ ELISA, data are represented as picograms of peptide present in milligrams of total protein. Luteolin treatment results in markedly reduced soluble Aβ1–40, 42 levels, 25% and 49%, respectively (top panel). No significant reductions in insoluble Aβ isoforms following treatment were observed (bottom panel).
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Chemical structures of the 5,7-dihydroxyflavone compounds.
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Oral administration of diosmin reduces Aβ pathology in Tg2576 mice. Brain homogenates and sections from Tg2576 mice treated with 0.05% diosmin supplemented diet (n= 10) or control diet (n= 10). For (A), half-brain coronal sections were analysed by Aβ antibody 4G8 staining. For (B), percentage of 4G8 positive plaques (mean ± S.E.M.) was quantified by image analysis. A t-test for independent samples revealed significant differences (P < 0.001) between groups. For (C), total soluble and insoluble Aβ1–40, 42 peptides from homogenates were analysed by ELISA. For Aβ ELISA, data are represented as picograms of peptide present in milligrams of total protein. Diosmin treatment results in markedly reduced total soluble and insoluble Aβ1–40, 42 levels, 37% and 46%, respectively. A t-test for independent samples revealed significant differences (P < 0.005) between groups.

References

    1. Funamoto S, Morishima-Kawashima M, Tanimura Y, Hirotani N, Saido TC, Ihara Y. Truncated carboxyl-terminal fragments of beta-amyloid precursor protein are processed to amyloid beta-proteins 40 and 42. Biochemistry. 2004;43:13532–40.
    1. Sambamurti K, Greig NH, Lahiri DK. Advances in the cellular and molecular biology of the beta-amyloid protein in Alzheimer's disease. Neuromol Med. 2002;1:1–31.
    1. Golde TE, Eckman CB, Younkin SG. Biochemical detection of Abeta isoforms: implications for pathogenesis, diagnosis, and treatment of Alzheimer's disease. Biochim Biophys Acta. 2000;1502:172–87.
    1. Huse JT, Doms RW. Closing in on the amyloid cascade: recent insights into the cell biology of Alzheimer's disease. Mol Neurobiol. 2000;22:81–98.
    1. Selkoe DL, Yamazaki T, Citron M, Podlisny MB, Koo EH, Teplow DB, Haass C. The role of APP processing and trafficking pathways in the formation of amyloid beta-protein. Ann NY Acad Sci. 1996;777:57–64.
    1. LaFerla FM, Tinkle BT, Bieberich CJ, Haudenschild CC, Jay G. The Alzheimer's A beta peptide induces neurodegeneration and apoptotic cell death in transgenic mice. Nat Genet. 1995;9:21–30.
    1. Loo DT, Copani A, Pike CJ, Whittemore ER, Walencewicz AJ, Cotman CW. Apoptosis is induced by beta-amyloid in cultured central nervous system neurons. Proc Natl Acad Sci USA. 1993;90:7951–5.
    1. Bradt BM, Kolb WP, Cooper NR. Complement-dependent proinflammatory properties of the Alzheimer's disease beta-peptide. J Exp Med. 1998;188:431–8.
    1. Suo Z, Tan J, Placzek A, Crawford F, Fang C, Mullan M. Alzheimer's beta-amyloid peptides induce inflammatory cascade in human vascular cells: the roles of cytokines and CD40. Brain Res. 1998;807:110–7.
    1. Murakami K, Irie K, Ohigashi H, Hara H, Nagao M, Shimizu T, Shirasawa T. Formation and stabilization model of the 42-mer Abeta radical: implications for the long-lasting oxidative stress in Alzheimer's disease. J Am Chem Soc. 2005;127:15168–74.
    1. Hensley K, Carney JM, Mattson MP, Aksenova M, Harris M, Wu JF, Floyd RA, Butterfield DA. A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease. Proc Natl Acad Sci USA. 1994;91:3270–4.
    1. Schenk DB, Rydel RE, May P, Little S, Panetta J, Lieberburg I, Sinha S. Therapeutic approaches related to amyloid-beta peptide and Alzheimer's disease. J Med Chem. 1995;38:4141–54.
    1. Sinha S, Lieberburg I. Cellular mechanisms of beta-amyloid production and secretion. Proc Natl Acad Sci USA. 1999;96:11049–53.
    1. Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the trans-membrane aspartic protease BACE. Science. 1999;286:735–41.
    1. Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, Brashier JR, Stratman NC, Mathews WR, Buhl AE, Carter DB, Tomasselli AG, Parodi LA, Heinrikson RL, Gurney ME. Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature. 1999;402:533–7.
    1. Steiner H, Duff K, Capell A, Romig H, Grim MG, Lincoln S, Hardy J, Yu X, Picciano M, Fechteler K, Citron M, Kopan R, Pesold B, Keck S, Baader M, Tomita T, Iwatsubo T, Baumeister R, Haass C. A loss of function mutation of presenilin-2 interferes with amyloid beta-peptide production and notch signaling. J Biol Chem. 1999;274:28669–73.
    1. 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;391:387–90.
    1. Citron M, Diehl TS, Gordon G, Biere AL, Seubert P, Selkoe DJ. Evidence that the 42- and 40-amino acid forms of amyloid beta protein are generated from the beta-amyloid precursor protein by different protease activities. Proc Natl Acad Sci USA. 1996;93:13170–5.
    1. Evin G, Cappai R, Li QX, Culvenor JG, Small DH, Beyreuther K, Masters CL. Candidate gamma-secretases in the generation of the carboxyl terminus of the Alzheimer's disease beta A4 amyloid: possible involvement of cathepsin D. Biochemistry. 1995;34:14185–92.
    1. Barten DM, Meredith JE, Jr, Zaczek R, Houston JG, Albright CF. Gamma-secretase inhibitors for Alzheimer's disease: balancing efficacy and toxicity. Drugs R D. 2006;7:87–97.
    1. Evin G, Sernee MF, Masters CL. Inhibition of gamma-secretase as a therapeutic intervention for Alzheimer's disease: prospects, limitations and strategies. CNS Drugs. 2006;20:351–72.
    1. Dovey HF, John V, Anderson JP, Chen LZ, De Saint Andrieu P, Fang LY, Freedman SB, Folmer B, Goldbach E, Holsztynska EJ, Hu KL, Johnson-Wood KL, Kennedy SL, Kholodenko D, Knops JE, Latimer LH, Lee M, Liao Z, Lieberburg IM, Motter RN, Mutter LC, Nietz J, Quinn KP, Sacchi KL, Seubert PA, Shopp GM, Thorsett ED, Tung JS, Wu J, Yang S, Yin CT, Schenk DB, May PC, Altstiel LD, Bender MH, Boggs LN, Britton TC, Clemens JC, Czilli DL, Dieckman-McGinty DK, Droste JJ, Fuson KS, Gitter BD, Hyslop PA, Johnstone EM, Li WY, Little SP, Mabry TE, Miller FD, Audia JE. Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J Neurochem. 2001;76:173–81.
    1. Citron M, Diehl TS, Capell A, Haass C, Teplow DB, Selkoe DJ. Inhibition of amyloid beta-protein production in neural cells by the serine protease inhibitor AEBSF. Neuron. 1996;17:171–9.
    1. Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F, Guido T, Hagopian K, Johnson-Wood K, Khan K, Lee M, Leibowitz P, Lieberburg I, Little S, Masliah E, McConlogue L, Montoya-Zavala M, Mucke L, Paganini L, Penniman E, Power M, Schenk D, Seubert P, Snyder B, Soriano F, Tan H, Vitale J, Wadsworth S, Wolozin B, Zhao J. Alzheimer-type neuropathology in trans-genic mice overexpressing V717F beta-amyloid precursor protein. Nature. 1995;373:523–7.
    1. Higaki L, Quon D, Zhong Z, Cordell B. Inhibition of beta-amyloid formation identifies proteolytic precursors and subcellu-lar site of catabolism. Neuron. 1995;14:651–9.
    1. Klafki HW, Paganetti PA, Sommer B, Staufenbiel M. Calpain inhibitor I decreases beta A4 secretion from human embryonal kidney cells expressing beta-amyloid precursor protein carrying the APP670/671 double mutation. Neurosci Lett. 1995;201:29–32.
    1. Comery TA, Martone RL, Aschmies S, Atchison KP, Diamantidis G, Gong X, Zhou H, Kreft AF, Pangalos MN, Sonnenberg-Reines J, Jacobsen JS, Marquis KL. Acute gamma-secretase inhibition improves contextual fear conditioning in the Tg2576 mouse model of Alzheimer's disease. J Neurosci. 2005;25:8898–902.
    1. Engel T, Hernandez F, Avila J, Lucas JJ. Full reversal of Alzheimer's disease-like phenotype in a mouse model with conditional overexpression of glycogen synthase kinase-3. J Neurosci. 2006;26:5083–90.
    1. Kozlovsky N, Belmaker RH, Agam G. Low GSK-3beta immunoreactivity in postmortem frontal cortex of schizophrenic patients. Am J Psychiatry. 2000;157:831–3.
    1. Carmichael J, Sugars KL, Bao YP, Rubinsztein DC. Glycogen synthase kinase-3beta inhibitors prevent cellular polyglutamine toxicity caused by the Huntington's disease mutation. J Biol Chem. 2002;277:33791–8.
    1. Agam G, Levine J. Glycogen synthase kinase-3 – a new target for lithium's effects in bipolar patients? Hum Psycho -pharmacol Clin Exp. 1998;13:463–5.
    1. Ishiguro K, Shiratsuchi A, Sato S, Omori A, Arioka M, Kobayashi S, Uchida T, Imahori K. Glycogen synthase kinase 3(3 is identical to tau protein kinase I generating several epitopes of paired helical filaments. FEBS Lett. 1993;325:167–72.
    1. Aplin AE, Gibb GM, Jacobsen JS, Gallo JM, Anderton BH. In vitro phosphorylation of the cytoplasmic domain of the amyloid precursor protein by glycogen synthase kinase-3β. J Neurochem. 1996;67:699–707.
    1. Takashima A, Noguchi K, Michel G, Mercken M, Hoshi M, Ishiguro K, Imahori K. Exposure of rat hippocampal neurons to amyloid β peptide (25–35) induces the inactivation of phosphatidylinositol-3 kinase and the activation of tau protein kinase 1/glycogen synthase kinase-3β. Neurosci Lett. 1996;203:33–6.
    1. Takashima A, Honda T, Yasutake K, Michel G, Murayama O, Murayama M, Ishiguro K, Yamaguchi H. Activation of tau protein kinase 1/glycogen synthase-3β by amyloid β peptide (25–35) enhances phosphorylation of tau in hippocampal neurons. Neurosci Res. 1998;32:317–23.
    1. Takashima A, Murayama M, Murayama O, Kohno T, Honda T, Yasutake K, Nihonmatsu N, Mercken M, Yamaguchi H, Sugihara S, Wolozin B. Presenilin 1 associates with glycogen synthase kinase-3(i and its substrate tau. Proc Natl Acad Sci USA. 1998;95:9637–41.
    1. Phiel CJ, Wilson CA, Lee VM, Klein PS. GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides. Nature. 2003;423:435–9.
    1. Barberger-Gateau P, Raffaitin C, Letenneur L, Berr C, Tzourio C, Dartigues JF, Alperovitch A. Dietary patterns and risk of dementia: the Three-City cohort study. Neurology. 2007;69:1921–30.
    1. Dai Q, Borenstein AR, Wu Y, Jackson JC, Larson EB. Fruit and vegetable juices and Alzheimer's disease: the Kame Project. Am J Med. 2006;119:751–9.
    1. Marambaud P, Zhao H, Davies P. Resveratrol promotes clearance of Alzheimer's disease amyloid-beta peptides. J Biol Chem. 2005;280:37377–82.
    1. Rezai-Zadeh K, Shytle D, Sun N, Mori T, Hou H, Jeanniton D, Ehrhart J, Townsend K, Zeng J, Morgan D, Hardy J, Town T, Tan J. Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloi- dosis in Alzheimer transgenic mice. J Neurosci. 2005;25:8807–14.
    1. Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, Chen PP, Kayed R, Glabe CG, Frautschy SA, Cole GM. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem. 2005;280:5892–901.
    1. Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G. Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science. 1996;274:99–102.
    1. Tan J, Town T, Crawford F, Mori T, DelleDonne A, Crescentini R, Obregon D, Flavell RA, Mullan MJ. Role of CD40 ligand in amyloidosis in transgenic Alzheimer's mice. Nat Neurosci. 2002;5:1288–93.
    1. Wittemer SM, Ploch M, Windeck T, Miiller SC, Drewelow B, Derendorf H, Veit M. Bioavailability and pharmacokinet-ics of caffeoylquinic acids and flavonoids after oral administration of Artichoke leaf extracts in humans. Phytomedicine. 2005;12:28–38.
    1. Shimoi K, Okada H, Furugori M, Goda T, Takase S, Suzuki M, Hara Y, Yamamoto H, Kinae N. Intestinal absorption of lute-olin and luteolin 7-O-beta-glucoside in rats and humans. FEBS Lett. 1998;438:220–4.
    1. Cova D, De Angelis L, Giavarini F, Palladini G, Perego R. Pharmacokinetics and metabolism of oral diosmin in healthy volunteers. Int J Clin Pharmacol Ther Toxicol. 1992;30:29–33.
    1. Hong M, Chen DC, Klein PS, Lee VM. Lithium reduces tau phosphorylation by inhibition of glycogen synthase kinase-3. J Biol Chem. 1997;272:25326–32.
    1. Munoz-Montano JR, Moreno FJ, Avila J, Diaz-Nido J. Lithium inhibits Alzheimer's disease-like tau protein phosphorylation in neurons. FEBS Lett. 1997;411:183–8.
    1. Shah S, Lee SF, Tabuchi K, Hao YH, Yu C, LaPlant Q, Ball H, Dan CE, 3rd, Sudhof T, Yu G. Nicastrin functions as a gamma-secretase-substrate receptor. Cell. 2005;122:435–47.
    1. Seeger M, Nordstedt C, Petanceska S, Kovacs DM, Gouras GK, Hahne S, Fraser P, Levesque L, Czernik AJ, George-Hyslop PS, Sisodia SS, Thinakaran G, Tanzi RE, Greengard P, Gandy S. Evidence for phosphorylation and oligomeric assembly of presenilin 1. Proc Natl Acad Sci USA. 1997;94:5090–4.
    1. Walter J, Grunberg J, Capell A, Pesold B, Schindzielorz A, Citron M, Mendla K, George-Hyslop PS, Multhaup G, Selkoe DJ, Haass Proteolytic processing of the Alzheimer disease-associated presenilin-1 generates an in vivo substrate for protein kinase C. Proc Natl Acad Sci USA. 1997;94:5349–54.
    1. Buxbaum JD, Gandy SE, Cicchetti P, Ehrlich ME, Czernik AJ, Fracasso RP, Ramabhadran TV, Unterbeck AJ, Greengard P. Processing of Alzheimer beta/A4 amyloid precursor protein: modulation by agents that regulate protein phosphorylation. Proc Natl Acad Sci USA. 1990;87:6003–6.
    1. Lopez-Perez E, Zhang Y, Frank SJ, Creemers J, Seidah N, Checler F. Constitutive alpha-secretase cleavage of the beta-amyloid precursor protein in the furin-deficient LoVo cell line: involvement of the pro-hormone convertase 7 and the disintegrin metalloprotease ADAM10. J Neurochem. 2001;76:1532–9.
    1. Buxbaum JD, Liu KN, Luo Y, Slack JL, Stocking KL, Peschon JJ, Johnson RS, Castner BJ, Cerretti DP, Black RA. Evidence that tumor necrosis factor a converting enzyme is involved in regulated α-secretase cleavage of the Alzheimer amyloid protein precursor. J Biol Chem. 1998;273:27765–7.
    1. Savage M, Trusko SP, Howland DS, Pinsker LR, Mistretta S, Reaume AG, Greenberg BD, Siman R, Scott RW. Turnover of amyloid β-protein in mouse brain and acute reduction of its level by phorbol ester. J Neurosci. 1998;18:1743–52.
    1. Checler F. Processing of the β-amyloid precursor protein and its regulation in Alzheimer's disease. J Neurochem. 1995;65:1431–44.
    1. Hung AY, Haass C, Nitsch RM, Qiu WQ, Citron M, Wurtman RJ, Growdon JH, Selkoe DJ. Activation of protein kinase C inhibits cellular production of the amyloid beta-protein. J Biol Chem. 1993;268:22959–62.
    1. Hyun SK, Jung HA, Chung HY, Choi JS. In vitro peroxynitrite scavenging activity of 6-hydroxykynurenic acid and other flavonoids from Gingko biloba yellow leaves. Arch Pharm Res. 2006;29:1074–9.
    1. Horvathova K, Novotny L, Tothova D, Vachalkova A. Determination of free radical scavenging activity of quercetin, rutin, luteolin and apigenin in H2O2-treated human ML cells K562. Neoplasma. 2004;51:395–9.
    1. Hougee S, Sanders A, Faber J, Graus YM, Van Den Berg WB, Garssen J, Smit HF, Hoijer MA. Decreased pro-inflammatory cytokine production by LPS-stimulated PBMC upon in vitro incubation with the flavonoids apigenin, luteolin or chrysin, due to selective elimination of mono-cytes/macrophages. Biochem Pharmacol. 2005;69:241–8.
    1. Verbeek R, Plomp AC, Van Tol EA, Van Noort JM. The flavones luteolin and apigenin inhibit in vitro antigen-specific proliferation and interferon-gamma production by murine and human autoimmune T cells. Biochem Pharmacol. 2004;68:621–9.
    1. Hirano T, Higa S, Arimitsu J, Naka T, Ogata A, Shima Y, Fujimoto M, Yamadori T, Ohkawara T, Kuwabara Y, Kawai M, Matsuda H, Yoshikawa M, Maezaki N, Tanaka T, Kawase I, Tanaka T. Luteolin, a flavonoid, inhibits AP-1 activation by basophils. Biochem Biophys Res Commun. 2006;340:1–7.
    1. Hirano T, Higa S, Arimitsu J, Naka T, Shima Y, Ohshima S, Fujimoto M, Yamadori T, Kawase I, Tanaka T. Flavonoids such as luteolin, fisetin and apigenin are inhibitors of interleukin-4 and interleukin-13 production by activated human basophils. Int Arch Allergy Immunol. 2004;134:135–40.
    1. Zhang F, Phiel CJ, Spece L, Gurvich N, Klein PS. Inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3) in response to lithium. Evidence for autoreg-ulation of GSK-3. J Biol Chem. 2003;278:33067–77.

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