Hyperphosphorylation of tau by GSK-3β in Alzheimer’s disease: The interaction of Aβ and sphingolipid mediators as a therapeutic target

[1] Hanger D.P., Anderton B.H., Noble W., Tau phosphorylation: the therapeutic challenge for neurodegenerative disease, Trends Mol. Med., 2009, 15, 112–119 10.1016/j.molmed.2009.01.003Search in Google Scholar

[2] Solfrizzi V., D’Introno A., Colacicco A.M., Capurso C., Del Parigi A., Capurso S., et al., Dietary fatty acids intake: possible role in cognitive decline and dementia, Exp. Gerontol., 2005, 40, 257–270 10.1016/j.exger.2005.01.001Search in Google Scholar

[3] Takechi R., Galloway S., Pallebage-Gamarallage M.M., Lam V., Mamo J.C., Dietary fats, cerebrovasculature integrity and Alzheimer’s disease risk, Prog. Lipid Res., 2010, 49, 159–170 10.1016/j.plipres.2009.10.004Search in Google Scholar

[4] Roher A.E., Weiss N., Kokjohn T.A., Kuo Y.M., Kalback W., Anthony J., et al., Increased Aβ peptides and reduced cholesterol and myelin proteins characterize white matter degeneration in Alzheimer’s disease, Biochemistry, 2002, 41, 11080–11090 10.1021/bi026173dSearch in Google Scholar

[5] Presečki P., Mück-Šeler D., Mimica N., Pivac N., Mustapić M., Stipčević T., et al., Serum Lipid Levels in Patients with Alzheimer’s Disease, 2011, Coll. Antropol., 35, Suppl. 1, 115–120 Search in Google Scholar

[6] Grundke-Iqbal I., Iqbal K., Quinlan M., Tung Y.-C., Zaidi M.S., Wisniewski H.M., Microtubule-associated protein tau. A component of Alzheimer paired helical filaments, J. Biol. Chem., 1986, 6084–6089 10.1016/S0021-9258(17)38495-8Search in Google Scholar

[7] Blennow K., de Leon M.J., Zetterberg H., Alzheimer’s disease, Lancet, 2006, 368, 387–403 10.1016/S0140-6736(06)69113-7Search in Google Scholar

[8] Gouras G.K., Tampellini D., Takahashi R.H., Capetillo-Zarate E., Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease, Acta Neuropathol., 2010, 119, 523–541 10.1007/s00401-010-0679-9Search in Google Scholar PubMed PubMed Central

[9] Šimić G., Gnjidić M., Kostović I., Cytoskeletal changes as an alternative view on pathogenesis of Alzheimer’s disease, Period. Biol., 1998, 100, 165–173 Search in Google Scholar

[10] Brandt R., Hundelt M., Shahani N., Tau alteration and neuronal degeneration in tauopathies: mechanisms and models, Biochim. Biophys. Acta, 2005, 1739, 331–354 10.1016/j.bbadis.2004.06.018Search in Google Scholar PubMed

[11] Rapoport M., Dawson H.N., Binder L.I., Vitek M.P., Ferreira A., Tau is essential to β-amyloid-induced neurotoxicity, Proc. Natl. Acad. Sci. USA, 2002, 99, 6364–6369 10.1073/pnas.092136199Search in Google Scholar PubMed PubMed Central

[12] Resende R., Ferreiro E., Pereira C., Resende Oliveira C., ER stress is involved in Aβ-induced GSK-3β activation and tau phosphorylation, J. Neurosci. Res., 2008, 86, 2091–2099 10.1002/jnr.21648Search in Google Scholar PubMed

[13] Huang H.C., Jiang Z.F., Accumulated amyloid-β peptide and hyperphosphorylated tau protein: relationship and links in Alzheimer’s disease, J. Alzheimers Dis., 2009, 16, 15–27 10.3233/JAD-2009-0960Search in Google Scholar PubMed

[14] Zhang Z., Zhao R., Qi J., Wen S., Tang Y., Wang D., Inhibition of glycogen synthase kinase-3β by Angelica sinensis extract decreases β-amyloid-induced neurotoxicity and tau phosphorylation in cultured cortical neurons, J. Neurosci. Res., 2011, 89, 437–447 10.1002/jnr.22563Search in Google Scholar PubMed

[15] Jin M., Shepardson N., Yang T., Chen G., Walsh D., Selkoe D.J., Soluble amyloid β-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration, Proc. Natl. Acad. Sci. USA, 2011, 108, 5819–5824 10.1073/pnas.1017033108Search in Google Scholar PubMed PubMed Central

[16] Chabrier M.A., Blurton-Jones M., Agazaryan A.A., Nerhus J.L., Martinez-Coria H., LaFerla F.M., Soluble Aβ promotes wild-type tau pathology in vivo, J. Neurosci., 2012, 32, 17345–17350 10.1523/JNEUROSCI.0172-12.2012Search in Google Scholar PubMed PubMed Central

[17] McKee A.C., Carreras I., Hossain L., Ryu H., Klein W.L., Oddo S., et al., Ibuprofen reduces Aβ, hyperphosphorylated tau and memory deficits in Alzheimer mice, Brain Res., 2008, 1207, 225–236 10.1016/j.brainres.2008.01.095Search in Google Scholar PubMed PubMed Central

[18] Lanzillotta A., Sarnico I., Benarese M., Branca C., Baiguera C., Hutter-Paier B., et al., The γ-secretase modulator CHF5074 reduces the accumulation of native hyperphosphorylated tau in a transgenic mouse model of Alzheimer’s disease, J. Mol. Neurosci., 2011, 45, 22–31 10.1007/s12031-010-9482-2Search in Google Scholar PubMed

[19] Hernandez P., Lee G., Sjoberg M., Maccioni R.B., Tau phosphorylation by cdk5 and Fyn in response to amyloid peptide Aβ25–35: involvement of lipid rafts, J. Alzheimers Dis., 2009, 16, 149–156 10.3233/JAD-2009-0933Search in Google Scholar PubMed

[20] Kawarabayashi T., Shoji M., Younkin L.H., Wen-Lang L., Dickson D.W., Murakami T., et al., Dimeric amyloid β protein rapidly accumulates in lipid rafts followed by apolipoprotein E and phosphorylated tau accumulation in the Tg2576 mouse model of Alzheimer’s disease, J. Neurosci., 2004, 24,15, 3801–3809 10.1523/JNEUROSCI.5543-03.2004Search in Google Scholar PubMed PubMed Central

[21] Grimm M.O.W., Rothhaar T.L., Hartmann T., The role of APP proteolytic processing in lipid metabolism, Exp. Brain Res., 2012, 217, 365–375 10.1007/s00221-011-2975-6Search in Google Scholar PubMed

[22] Aronov S., Aranda G., Behar L., Ginzburg I., Visualization of translated tau protein in the axons of neuronal P19 cells and characterization of tau RNP granules, J. Cell Sci., 2002, 115, 3817–3827 10.1242/jcs.00058Search in Google Scholar PubMed

[23] Esmaeli-Azad B., McCarty J.H., Feinstein S.C., Sense and antisense transfection analysis of tau function: tau influences net microtubule assembly, neurite outgrowth and neuritic stability, J. Cell Sci., 1994, 107, 869–879 10.1242/jcs.107.4.869Search in Google Scholar

[24] Šimić G., Stanić G., Mladinov M., Jovanov-Milošević N., Kostović I., Hof P.R., Does Alzheimer’s disease begin in the brainstem?, Neuropathol. Appl. Neurobiol., 2009, 35, 532–554 10.1111/j.1365-2990.2009.01038.xSearch in Google Scholar

[25] Takuma H., Arawaka S., Mori H., Isoforms changes of tau protein during development in various species, Dev. Brain Res., 2003, 142, 121–127 10.1016/S0165-3806(03)00056-7Search in Google Scholar

[26] Deshpande A., Win K.M., Busciglio J., Tau isoform expression and regulation in human cortical neurons, FASEB J., 2008, 22, 2357–2367 10.1096/fj.07-096909Search in Google Scholar

[27] Jovanov-Milošević N., Petrović D., Sedmak G., Vukšić M., Hof P.R., Šimić G., Human fetal tau protein isoform: possibilities for Alzheimer’s disease treatment, Int. J. Biochem. Cell. Biol., 2012, 44, 1290–1294 10.1016/j.biocel.2012.05.001Search in Google Scholar

[28] Lee G., Neve R.L., Kosik K.S., The microtubule binding domain of tau protein, Neuron, 1989, 2, 1615–1624 10.1016/0896-6273(89)90050-0Search in Google Scholar

[29] Buée L., Bussière T., Buée-Scherrer V., Delacourte A., Hof P.R., Tau protein isoforms, phosphorylation and role in neurodegenerative disorders, Brain Res. Rev., 2000, 33, 95–130 10.1016/S0165-0173(00)00019-9Search in Google Scholar

[30] Ballatore C., Lee V.M., Trojanowski J.Q., Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders, Nat. Rev. Neurosci., 2007, 8, 663–672 10.1038/nrn2194Search in Google Scholar PubMed

[31] Adams S.J., DeTure M.A., McBride M., Dickson D.W., Petrucelli L., Three repeat isoforms of tau inhibit assembly of four repeat tau filaments, PLoS One, 2010, 5, e10810 10.1371/journal.pone.0010810Search in Google Scholar PubMed PubMed Central

[32] Johnson G.V., Stoothoff W.H., Tau phosphorylation in neuronal cell function and dysfunction, J. Cell Sci., 2004, 117, 5721–5729 10.1242/jcs.01558Search in Google Scholar PubMed

[33] Iqbal K., Liu F., Gong C.X., Grundke-Iqbal I., Tau in Alzheimer disease and related tauopathies, Curr. Alzheimer Res., 2010, 7, 656–664 10.2174/156720510793611592Search in Google Scholar PubMed PubMed Central

[34] Morishima-Kawashima M., Hasegawa M., Takio K., Suzuki M., Yoshida H., Titani K., et al., Proline-directed and non-proline-directed phosphorylation of PHF-tau, J. Biol. Chem., 1995, 270, 823–829 10.1074/jbc.270.2.823Search in Google Scholar PubMed

[35] Wang J.Z., Xia Y.Y., Grundke-Iqbal I., Iqbal K., Abnormal hyperphosphorylation of tau: sites, regulation, and molecular mechanism of neurofibrillary degeneration, J. Alzheimers Dis., 2013, Suppl 1, S123–S139 10.3233/JAD-2012-129031Search in Google Scholar PubMed

[36] Gray E.G., Paula-Barbosa M., Roher A., Alzheimer’s disease: paired helical filaments and cytomembranes, Neuropathol. Appl. Neurobiol., 1987, 13, 91–110 10.1111/j.1365-2990.1987.tb00174.xSearch in Google Scholar PubMed

[37] Jenkins S.M., Johnson G.V., Modulation of tau phosphorylation within its microtubule-binding domain by cellular thiols, J. Neurochem., 1999, 73, 1843–1850 10.1046/j.1471-4159.1999.01843.xSearch in Google Scholar

[38] Cho J.-H., Johnson G.V.W., Primed phosphorylation of tau at Thr231 by glycogen synthase kinase 3β (GSK3β) plays a critical role in regulating tau’s ability to bind and stabilize microtubules, J. Neurochem., 2004, 88, 349–358 10.1111/j.1471-4159.2004.02155.xSearch in Google Scholar PubMed

[39] Alonso A.D., Di Clerico J., Li B., Corbo C.P., Alaniz M.E., Grundke-Iqbal I., et al., Phosphorylation of tau at Thr212, Thr231, and Ser262 combined causes neurodegeneration, J. Biol. Chem., 2010, 285, 30851–30860 10.1074/jbc.M110.110957Search in Google Scholar PubMed PubMed Central

[40] Iijima-Ando K., Sekiya M., Maruko-Otake A., Ohtake Y., Suzuki E., Lu B., et al., Loss of axonal mitochondria promotes taumediated neurodegeneration and Alzheimer’s disease-related tau phosphorylation via PAR-1, PLoS Genet., 2012, 8, e1002918 10.1371/journal.pgen.1002918Search in Google Scholar PubMed PubMed Central

[41] Alonso A.C, Zaidi T., Novak M., Grundke-Iqbal I., Iqbal K., Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments, Proc. Natl. Acad. Sci. USA, 2001, 98, 6923–6928 10.1073/pnas.121119298Search in Google Scholar PubMed PubMed Central

[42] Kimura T., Ono T., Takamatsu J., Yamamoto H., Ikegami K., Kondo A., et al., Sequential changes of tau-site-specific phosphorylation during development of paired helical filaments, Dementia, 1996, 7, 177–181 10.1159/000106875Search in Google Scholar PubMed

[43] Augustinack J.C., Schneider A., Mandelkow E.-M., Hyman B.T., Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer’s disease, Acta Neuropathol., 2002, 103, 26–35 10.1007/s004010100423Search in Google Scholar

[44] Arnold S.E., Hyman B.T., Flory J., Damasio A.R., Van Hoesen G.W., The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer’s disease, Cereb. Cortex, 1991, 1, 103–116 10.1093/cercor/1.1.103Search in Google Scholar

[45] Braak H., Braak E., Neuropathological stageing of Alzheimer-related changes, Acta Neuropathol., 1991, 82, 239–259 10.1007/BF00308809Search in Google Scholar

[46] Šimić G., Kostović I., Winblad B., Bogdanović N., Volume and number of neurons of the human hippocampal formation in normal aging and Alzheimer’s disease, J. Comp. Neurol., 1997, 379, 482–494 10.1002/(SICI)1096-9861(19970324)379:4<482::AID-CNE2>3.0.CO;2-ZSearch in Google Scholar

[47] Šimić G., Bexheti S., Kelović Z., Kos M., Grbić K., Hof P.R., et al., Hemispheric asymmetry, modular variability and age-related changes in the human entorhinal cortex, Neuroscience, 2005, 130, 911–25 10.1016/j.neuroscience.2004.09.040Search in Google Scholar

[48] Braak H., Thal D.R., Ghebremedhin E., Del Tredici K., Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years, J. Neuropathol. Exp. Neurol., 2011, 70, 960–969 10.1097/NEN.0b013e318232a379Search in Google Scholar

[49] Watanabe A., Hasegawa M., Suzuki M., Takio K., Morishima-Kawashima M., Titani K., et al., In vivo phosphorylation sites in fetal and adult rat tau, J. Biol. Chem., 1993, 268, 25712–25717 10.1016/S0021-9258(19)74447-0Search in Google Scholar

[50] Avila J., Tau phosphorylation and aggregation in Alzheimer’s disease pathology, FEBS Lett., 2006, 580, 2922–2927 10.1016/j.febslet.2006.02.067Search in Google Scholar

[51] Ferrer I., Gomez-Isla T., Puig B., Freixes M., Ribé E., Dalfó E., et al., Current advances on different kinases involved in tau phosphorylation, and implications in Alzheimer’s disease and tauopathies, Curr. Alzheimer Res., 2005, 2, 3–18 10.2174/1567205052772713Search in Google Scholar

[52] Michel G., Mercken M., Murayama M., Noguchi K., Ishiguro K., Imahori K., et al., Characterization of tau phosphorylation in glycogen synthase kinase-3β and cyclin dependent kinase-5 activator (p23) transfected cells, Biochim. Biophys. Acta, 1998, 1380, 177–182 10.1016/S0304-4165(97)00139-6Search in Google Scholar

[53] Maccioni R.B., Otth C., Concha I.I., Muñoz J.P., The protein kinase Cdk5. Structural aspects, roles in neurogenesis and involvement in Alzheimer’s pathology, Eur. J. Biochem., 2001, 268, 1518–1527 10.1046/j.1432-1327.2001.02024.xSearch in Google Scholar

[54] Li G., Yin H., Kuret J., Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules, J. Biol. Chem., 2004, 279, 15938–15945 10.1074/jbc.M314116200Search in Google Scholar

[55] Lebouvier T., Scales T.M., Williamson R., Noble W., Duyckaerts C., Hanger D.P et al., The microtubule-associated protein tau is also phosphorylated on tyrosine, J. Alzheimers Dis., 2009, 18, 1–9 10.3233/JAD-2009-1116Search in Google Scholar

[56] Cai Z., Yan L.-J., Li K., Quazi S.H., Zhao B., Roles of AMP-activated protein kinase in Alzheimer’s disease, Neuromol. Med., 2012, 14, 1–14 10.1007/s12017-012-8173-2Search in Google Scholar

[57] Martin L., Latypova X., Wilson C.M., Magnaudeix A., Perrin M.L., Yardin C., et al., Tau protein kinases: involvement in Alzheimer’s disease, Ageing Res. Rev., 2013, 12, 289–309 10.1016/j.arr.2012.06.003Search in Google Scholar

[58] Martin L., Magnaudeix A., Esclaire F., Yardin C., Terro F., Inhibition of glycogen synthase kinase-3β downregulates total tau proteins in cultured neurons and its reversal by the blockade of protein phosphatase-2A, Brain Res., 2009, 1252, 66–75 10.1016/j.brainres.2008.11.057Search in Google Scholar

[59] Matsuo E.S., Shin R.W., Billingsley M.L., Van de Voorde A., O’Connor M., Trojanowski J.Q., et al., Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer’s disease paired helical filament tau, Neuron, 1994, 13, 989–1002 10.1016/0896-6273(94)90264-XSearch in Google Scholar

[60] Martin L., Latypova X., Wilson C.M., Magnaudeix A., Perrin M.L., Terro F., Tau protein phosphatases in Alzheimer’s disease: the leading role of PP2A, Ageing Res Rev., 2013, 12, 39–49 10.1016/j.arr.2012.06.008Search in Google Scholar PubMed

[61] Yamaguchi H., Ishiguro K., Uchida T., Takashima A., Lemere C.A., Imahori K., Preferential labeling of Alzheimer neurofibrillary tangles with antisera for tau protein kinase (TPK) I/glycogen synthase kinase-3 β and cyclin-dependent kinase 5, a component of TPK II, Acta Neuropathol., 1996, 92, 232–241 10.1007/s004010050513Search in Google Scholar PubMed

[62] Pei J.J., Braak E., Braak H., Grundke-Iqbal I., Iqbal K., Winblad B., et al., Distribution of active glycogen synthase kinase 3β (GSK-3 β) in brains staged for Alzheimer disease neurofibrillary changes, J. Neuropathol. Exp. Neurol., 1999, 58, 1010–1019 10.1097/00005072-199909000-00011Search in Google Scholar PubMed

[63] Leroy K., Yilmaz Z., Brion J.P., Increased level of active GSK-3β in Alzheimer’s disease and accumulation in argyrophilic grains and in neurones at different stages of neurofibrillary degeneration, Neuropathol. Appl. Neurobiol., 2007, 33, 43–55 10.1111/j.1365-2990.2006.00795.xSearch in Google Scholar

[64] Phiel C.J., Wilson C.A., Lee V.M., Klein P.S., GSK-3α regulates production of Alzheimer’s disease amyloid-beta peptides, Nature, 2003, 423, 435–439 10.1038/nature01640Search in Google Scholar

[65] Wagner U., Utton M., Gallo J.-M., Miller C.C.J., Cellular phosphorylation of tau by GSK-3β influences tau binding to microtubules and microtubule organisation, J. Cell Sci., 1996, 109, 1537–1543 10.1242/jcs.109.6.1537Search in Google Scholar

[66] Muñoz-Montaño J.R., Moreno F.J., Avila J., Diaz-Nido J., Lithium inhibits Alzheimer’s disease-like tau protein phosphorylation in neurons, FEBS Lett., 1997, 411, 183–188 10.1016/S0014-5793(97)00688-1Search in Google Scholar

[67] Cuchillo-Ibanez I., Seereeram A., Byers H.L., Leung K.Y., Ward M.A., Anderton B.H., et al., Phosphorylation of tau regulates its axonal transport by controlling its binding to kinesin, FASEB J., 2008, 22, 3186–3195 10.1096/fj.08-109181Search in Google Scholar

[68] Li T., Hawkes C., Qureshi H.Y., Kar S., Paudel H.K., Cyclin-dependent protein kinase 5 primes microtubule-associated protein tau sitespecifically for glycogen synthase kinase 3β, Biochemistry, 2006, 45, 3134–3145 10.1021/bi051635jSearch in Google Scholar

[69] Terwel D., Muyllaert D., Dewachter I., Borghgraef P., Croes S., Devijver H., et al., Amyloid activates GSK-3β to aggravate neuronal tauopathy in bigenic mice, Am. J. Pathol., 2008, 172, 786–798 10.2353/ajpath.2008.070904Search in Google Scholar

[70] Noble W., Olm V., Takata K., Casey E., Mary O., Meyerson J., et al., Cdk5 is a key factor in tau aggregation and tangle formation in vivo, Neuron, 2003, 38, 555–565 10.1016/S0896-6273(03)00259-9Search in Google Scholar

[71] Rankin C.A., Sun Q., Gamblin T.C., Tau phosphorylation by GSK-3β promotes tangle-like filament morphology, Mol. Neurodeg., 2007, 2, 12 10.1186/1750-1326-2-12Search in Google Scholar PubMed PubMed Central

[72] Lee C.W., Lau K.F., Miller C.C., Shaw P.C., Glycogen synthase kinase-3β-mediated tau phosphorylation in cultured cell lines, Neuroreport, 2003, 14, 257–260 10.1097/00001756-200302100-00020Search in Google Scholar PubMed

[73] Liu S.J., Zhang A.H., Li H.L., Wang Q., Deng H.M., Netzer W.J., et al., Overactivation of glycogen synthase kinase-3 by inhibition of phosphoinositol-3 kinase and protein kinase C leads to hyperphosphorylation of tau and impairment of spatial memory, J. Neurochem., 2003, 87, 1333–1344 10.1046/j.1471-4159.2003.02070.xSearch in Google Scholar PubMed

[74] Su Y., Ryder J., Li B., Wu X., Fox N., Solenberg P., et al., Lithium, a common drug for bipolar disorder treatment, regulates amyloid-β precursor protein processing, Biochemistry, 2004, 43, 6899–6908 10.1021/bi035627jSearch in Google Scholar PubMed

[75] Takashima A., Murayama M., Murayama O., Kohno T., Honda T., Yasutake K., et al., Presenilin 1 associates with glycogen synthase kinase-3β and its substrate tau, Proc. Natl. Acad. Sci. USA, 1998, 95, 9637–9641 10.1073/pnas.95.16.9637Search in Google Scholar PubMed PubMed Central

[76] Metcalfe M.J., Figueiredo-Pereira M.E., Relationship between tau pathology and neuroinflammation in Alzheimer’s disease, Mt. Sinai J. Med., 2010, 77, 50–58 10.1002/msj.20163Search in Google Scholar PubMed PubMed Central

[77] Parr C., Carzaniga R., Gentleman S.M., Van Leuven F., Walter J., Sastre M., Glycogen synthase kinase 3 inhibition promotes lysosomal biogenesis and autophagic degradation of the amyloid-β precursor protein, Mol. Cell. Biol., 2012, 32, 4410–4418 10.1128/MCB.00930-12Search in Google Scholar PubMed PubMed Central

[78] Noble W., Planel E., Zehr C., Olm V., Meyerson J., Suleman F., et al., Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo, Proc. Natl. Acad. Sci. USA, 2005, 102, 6990–6995 10.1073/pnas.0500466102Search in Google Scholar PubMed PubMed Central

[79] Zhao L., Wang F., Gui B., Hua F., Qian Y., Prophylactic lithium alleviates postoperative cognition impairment by phosphorylating hippocampal glycogen synthase kinase-3β (Ser9) in aged rats, Exp. Gerontol., 2011, 46, 1031–1036 10.1016/j.exger.2011.09.002Search in Google Scholar PubMed

[80] Caccamo A., Oddo S., Tran L.X., LaFerla F.M., Lithium reduces tau phosphorylation but not Aβ or working memory deficits in a transgenic model with both plaques and tangles, Am. J. Pathol., 2007, 170, 1669–1675 10.2353/ajpath.2007.061178Search in Google Scholar PubMed PubMed Central

[81] Serenó L., Coma M., Rodríguez M., Sánchez-Ferrer P., Sánchez M.B., Gich I., et al., A novel GSK-3β inhibitor reduces Alzheimer’s pathology and rescues neuronal loss in vivo, Neurobiol. Dis., 2009, 35, 359–367 10.1016/j.nbd.2009.05.025Search in Google Scholar PubMed

[82] Medina M., Castro A., Glycogen synthase kinase-3 (GSK-3) inhibitors reach the clinic, Curr. Opin. Drug Disc. Dev., 2008, 11, 533–543 Search in Google Scholar

[83] Kramer T., Schmidt B., Lo Monte F., Small-molecule inhibitors of GSK-3: structural insights and their application to Alzheimer’s disease models, Int. J. Alzheimers Dis., 2012, 381029 10.1155/2012/381029Search in Google Scholar PubMed PubMed Central

[84] Fumagalli F., Racagni G., Riva M.A., The expanding role of BDNF: a therapeutic target for Alzheimer’s disease?, Pharmacogenomics J., 2006, 6, 8–15 10.1038/sj.tpj.6500337Search in Google Scholar PubMed

[85] Blurton-Jones M., Kitazawa M., Martinez-Coria H., Castello N.A., Müller F.J., Loring J.F., et al., Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease, Proc. Natl. Acad. Sci. USA, 2009, 106, 13594–13599 10.1073/pnas.0901402106Search in Google Scholar PubMed PubMed Central

[86] Elliott E., Atlas R., Lange A., Ginzburg I., Brain-derived neurotrophic factor induces a rapid dephosphorylation of tau protein through a PI-3Kinase signalling mechanism, Eur. J. Pharmacol., 2005, 22, 1081–1089 10.1111/j.1460-9568.2005.04290.xSearch in Google Scholar PubMed

[87] Tong L., Balazs R., Thornton P.L., Cotman C.W., β-amyloid peptide at sublethal concentrations downregulates brain-derived neurotrophic factor functions in cultured cortical neurons, J. Neurosci., 2004, 24, 6799–6809 10.1523/JNEUROSCI.5463-03.2004Search in Google Scholar PubMed PubMed Central

[88] Magrané J., Rosen K.M., Smith R.C., Walsh K., Gouras G.K., Querfurth H.W., Intraneuronal β-amyloid expression downregulates the Akt survival pathway and blunts the stress response, J. Neurosci., 2005, 25, 10960–10969 10.1523/JNEUROSCI.1723-05.2005Search in Google Scholar PubMed PubMed Central

[89] Baki L., Shioi J., Wen P., Shao Z., Schwarzman A., Gama-Sosa M., et al., PS1 activates PI3K thus inhibiting GSK-3 activity and tau overphosphorylation: effects of FAD mutations, EMBO J., 2004, 23, 2586–2596 10.1038/sj.emboj.7600251Search in Google Scholar PubMed PubMed Central

[90] Jana A., Hogan E.L., Pahan K., Ceramide and neurodegeneration: susceptibility of neurons and oligodendrocytes to cell damage and death, J. Neurol. Sci., 2009, 278, 5–15 10.1016/j.jns.2008.12.010Search in Google Scholar PubMed PubMed Central

[91] Ben-David O., Futerman A.H., The role of the ceramide acyl chain length in neurodegeneration: involvement of ceramide synthases, Neuromolecular. Med., 2010, 12, 341–350 10.1007/s12017-010-8114-xSearch in Google Scholar PubMed

[92] Rao R.P., Vaidyanathan N., Rengasamy M., Oommen A.M., Somaiya N., Jagannath M.R., Sphingolipid metabolic pathway: an overview of major roles played in human diseases, J. Lipids, 2013, 178910 10.1155/2013/178910Search in Google Scholar PubMed PubMed Central

[93] Haughey N.J., Bandaru V.V., Bae M., Mattson M.P., Roles for dysfunctional sphingolipid metabolism in Alzheimer’s disease neuropathogenesis, Biochim. Biophys. Acta, 2010, 1801, 878–886 10.1016/j.bbalip.2010.05.003Search in Google Scholar PubMed PubMed Central

[94] Mielke M.M., Lyketsos C.G., Alterations of the sphingolipid pathway in Alzheimer’s disease: new biomarkers and treatment targets?, Neuromol. Med., 2010, 12, 331–340 10.1007/s12017-010-8121-ySearch in Google Scholar PubMed PubMed Central

[95] Mielke M.M., Haughey N.J., Could plasma sphingolipids be diagnostic or prognostic biomarkers for Alzheimer’s disease?, Clin. Lipidol., 2012, 7, 525–536 10.2217/clp.12.59Search in Google Scholar PubMed PubMed Central

[96] Gomez-Brouchet A., Pchejetski D., Brizuela L., Garcia V., Altié M.F., Maddelein M.L., et al., Critical role for sphingosine kinase-1 in regulating survival of neuroblastoma cells exposed to amyloid-β peptide, Mol. Pharmacol., 2007, 72, 341–349 10.1124/mol.106.033738Search in Google Scholar PubMed

[97] Seyb K.I., Ansar S., Li G., Bean J., Michaelis M.L., Dobrowsky R.T., p35/Cyclin-dependent kinase 5 is required for protection against beta-amyloid-induced cell death but not tau phosphorylation by ceramide, J. Mol. Neurosci., 2007, 31, 23–35 10.1007/BF02686115Search in Google Scholar PubMed

[98] Barth B.M., Gustafson S.J, Kuhn T.B., Neutral sphingomyelinase activation precedes NADPH oxidase-dependent damage in neurons exposed to the proinflammatory cytokine TNFα, J. Neurosci. Res., 2012, 90, 229–242 10.1002/jnr.22748Search in Google Scholar PubMed PubMed Central

[99] Grösch S., Schiffmann S., Geisslinger G., Chain length-specific properties of ceramides, Prog. Lipid Res., 2012, 51, 50–62 10.1016/j.plipres.2011.11.001Search in Google Scholar PubMed

[100] Katsel P., Li C., Haroutunian V., Gene expression alterations in the sphingolipid metabolism pathways during progression of dementia and Alzheimer’s disease: a shift toward ceramide accumulation at the earliest recognizable stages of Alzheimer’s disease?, Neurochem. Res., 2007, 32, 845–856 10.1007/s11064-007-9297-xSearch in Google Scholar PubMed

[101] Tamboli I.Y., Prager K., Barth E., Heneka M., Sandhoff K., Walter J., Inhibition of glycosphingolipid biosynthesis reduces secretion of the β-amyloid precursor protein and amyloid β -peptide, J. Biol. Chem., 2005, 280, 28110–28117 10.1074/jbc.M414525200Search in Google Scholar PubMed

[102] Kosicek M., Zetterberg H., Andreasen N., Peter-Katalinic J., Hecimovic S., Elevated cerebrospinal fluid sphingomyelin levels in prodromal Alzheimer’s disease, Neurosci. Lett., 2012, 516, 302–305 10.1016/j.neulet.2012.04.019Search in Google Scholar PubMed

[103] Mielke M.M., Haughey N.J., Bandaru V.V., Weinberg D.D., Darby E., Zaidi N., et al., Plasma sphingomyelins are associated with cognitive progression in Alzheimer’s disease, J. Alzheimers Dis., 2011, 27, 259–269 10.3233/JAD-2011-110405Search in Google Scholar PubMed PubMed Central

[104] Takasugi N., Sasaki T., Suzuki K., Osawa S., Isshiki H., Hori Y., et al., BACE1 activity is modulated by cell-associated sphingosine-1-phosphate, J. Neurosci., 2011, 31, 6850–6857 10.1523/JNEUROSCI.6467-10.2011Search in Google Scholar PubMed PubMed Central

[105] Yanagisawa K., Odaka A., Suzuki N., Ihara Y., GM1 gangliosidebound amyloid β-protein (Aβ): a possible form of preamyloid in Alzheimer’s disease, Nat. Med., 1995, 1, 1062–1066 10.1038/nm1095-1062Search in Google Scholar PubMed

[106] Utsumi M., Yamaguchi Y., Sasakawa H., Yamamoto N., Yanagisawa K., Kato K., Up-and-down topological mode of amyloid β-peptide lying on hydrophilic/hydrophobic interface of ganglioside clusters, Glycoconj. J., 2009, 26, 999–1006 10.1007/s10719-008-9216-7Search in Google Scholar PubMed

[107] Grimm M.O.W., Zimmer V.C., Lehmann J., Grimm H.S., Hartmann T., The impact of cholesterol, DHA, and sphingolipids on Alzheimer’s disease, BioMed Res. Int., 2013, 814390 10.1155/2013/814390Search in Google Scholar PubMed PubMed Central

[108] Han X., Holtzman M.D., McKeel D.W. Jr., Kelley J., Morris J.C., Substantial sulfatide deficiency and ceramide elevation in very early Alzheimer’s disease: potential role in disease pathogenesis, J. Neurochem., 2002, 82, 809–818 10.1046/j.1471-4159.2002.00997.xSearch in Google Scholar PubMed

[109] Kawakami F., Yamaguchi A., Suzuki K., Yamamoto T., Ohtsuki K., Biochemical characterization of phospholipids, sulfatide and heparin as potent stimulators for autophosphorylation of GSK-3β and the GSK-3β -mediated phosphorylation of myelin basic protein in vitro, J. Biochem., 2008, 143, 359–367 10.1093/jb/mvm228Search in Google Scholar PubMed

[110] Mielke M.M., Bandaru V.V., Haughey N.J., Xia J., Fried L.P., Yasar S., et al., Serum ceramides increase the risk of Alzheimer disease: the Women’s Health and Aging Study II, Neurology, 2012, 79, 633–641 10.1212/WNL.0b013e318264e380Search in Google Scholar PubMed PubMed Central

[111] Cutler R.G., Kelly J., Storie K., Pedersen W.A., Tammara A., Hatanpaa K., et al., Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer’s disease, Proc. Natl. Acad. Sci. USA, 2004, 17, 2070–2075 10.1073/pnas.0305799101Search in Google Scholar PubMed PubMed Central

[112] He X., Huang Y., Li B., Gong C.X., Schuchman E.H., Deregulation of sphingolipid metabolism in Alzheimer’s disease, Neurobiol. Aging, 2010, 31, 398–408 10.1016/j.neurobiolaging.2008.05.010Search in Google Scholar PubMed PubMed Central

[113] Filippov V., Song M.A., Zhang K., Vinters H.V., Tung S., Kirsch W.M., et al., Increased ceramide in brains with Alzheimer’s and other neurodegenerative diseases, J. Alzheimers Dis., 2012, 29, 537–547 10.3233/JAD-2011-111202Search in Google Scholar PubMed PubMed Central

[114] Toman R.E., Movsesyan V., Murthy S.K., Milstien S., Spiegel S., Faden A.I., Ceramide-induced cell death in primary neuronal cultures: upregulation of ceramide levels during neuronal apoptosis, J. Neurosci. Res., 2002, 68, 323–330 10.1002/jnr.10190Search in Google Scholar PubMed

[115] Zhang X., Wu J., Dou Y., Xia B., Rong W., Rimbach G., et al., Asiatic acid protects primary neurons against C2-ceramide-induced apoptosis, Eur. J. Pharmacol., 2012, 679, 51–59 10.1016/j.ejphar.2012.01.006Search in Google Scholar PubMed

[116] Ruvolo P.P., Deng X., Ito T., Carr B.K., May W.S., Ceramide induces Bcl2 dephosphorylation via a mechanism involving mitochondrial PP2A, J. Biol. Chem., 1999, 274, 20296–20300 10.1074/jbc.274.29.20296Search in Google Scholar PubMed

[117] Puglielli L., Ellis B.C., Saunders A.J., Kovacs D.M., Ceramide stabilizes β-site amyloid precursor protein-cleaving enzyme 1 and promotes amyloid β-peptide biogenesis, J. Biol. Chem., 2003, 30, 19777–19783 10.1074/jbc.M300466200Search in Google Scholar PubMed

[118] Patil S., Melrose J., Chan C., Involvement of astroglial ceramide in palmitic acid-induced Alzheimer-like changes in primary neurons, Eur. J. Neurosci., 2007, 26, 2131–2141 10.1111/j.1460-9568.2007.05797.xSearch in Google Scholar PubMed PubMed Central

[119] Jana A., Pahan K., Fibrillar amyloid-β peptides kill human primary neurons via NADPH oxidase-mediated activation of neutral sphingomyelinase. Implications for Alzheimer’s disease, J. Biol. Chem., 2004, 279, 51451–51459 10.1074/jbc.M404635200Search in Google Scholar PubMed PubMed Central

[120] Malaplate-Armand C., Florent-Béchard S., Youssef I., Koziel V., Sponne I., Kriem B., et al., Soluble oligomers of amyloid-β peptide induce neuronal apoptosis by activating a cPLA2-dependent sphingomyelinaseceramide pathway, Neurobiol. Dis., 2006, 23, 178–189 10.1016/j.nbd.2006.02.010Search in Google Scholar PubMed

[121] Geekiyanage H., Upadhye A., Chan C., Inhibition of serine palmitoyltransfrase reduces Aβ and tau hyperphosphorylation in a murine model: a safe therapeutic strategy for Alzheimer’s disease, Neurobiol. Aging, 2013, 34, 2037–2051 10.1016/j.neurobiolaging.2013.02.001Search in Google Scholar PubMed PubMed Central

[122] Jana A., Pahan K., Fibrillar amyloid-β-activated human astroglia kill primary human neurons via neutral sphingomyelinase: implications for Alzheimer’s disease, J. Neurosci., 2010, 30, 12676–12689 10.1523/JNEUROSCI.1243-10.2010Search in Google Scholar PubMed PubMed Central

[123] Liu L., Martin R., Chan C., Palmitate-activated astrocytes via serine palmitoyl transferase increase BACE1 in primary neurons by sphingomyelinases, Neurobiol. Aging, 2013, 34, 540–550 10.1016/j.neurobiolaging.2012.05.017Search in Google Scholar PubMed PubMed Central

[124] Patil S., Sheng L., Masserang A., Chan C., Palmitic acid-treated astrocytes induce BACE1 upregulation and accumulation of C-terminal fragment of APP in primary cortical neurons, Neurosci. Lett., 2006, 406, 55–99 10.1016/j.neulet.2006.07.015Search in Google Scholar PubMed

[125] Grimm M.O., Grösgen S., Rothhaar T.L., Burg V.K., Hundsdörfer B., Haupenthal V.J., et al., Intracellular APP domain regulates serinepalmitoyl-CoA transferase expression and is affected in Alzheimer’s disease, Int. J. Alzheimers Dis., 2011, 695413 10.4061/2011/695413Search in Google Scholar PubMed PubMed Central

[126] Tsai G.E., Falk W.E., Gunther J., Coyle J.T., Improved cognition in Alzheimer’s disease with short-term D-cycloserine treatment, Am. J. Psychiatry, 1999, 156, 467–469 Search in Google Scholar

[127] Mukhopadhyay A., Saddoughi S.A., Song P., Sultan I., Ponnusamy S., Senkal C.E., et al., Direct interaction between the inhibitor 2 and ceramide via sphingolipid-protein binding is involved in the regulation of protein phosphatase 2A activity and signaling, FASEB J., 2009, 23, 751–763 10.1096/fj.08-120550Search in Google Scholar PubMed PubMed Central

[128] Darios F., Muriel M.P., Khondiker M.E., Brice A., Ruberg M., Neurotoxic calcium transfer from endoplasmic reticulum to mitochondria is regulated by cyclin-dependent kinase 5-dependent phosphorylation of tau, J. Neurosci., 2005, 25, 4159–4168 10.1523/JNEUROSCI.0060-05.2005Search in Google Scholar PubMed PubMed Central

[129] Pérez M., Hernández F., Lim F., Díaz-Nido J., Avila J., Chronic lithium treatment decreases mutant tau protein aggregation in a transgenic mouse model, J. Alzheimers Dis., 2003, 5, 301–308 10.3233/JAD-2003-5405Search in Google Scholar PubMed

[130] Nakashima H., Ishihara T., Suguimoto P., Yokota O., Oshima E., Kugo A., et al., Chronic lithium treatment decreases tau lesions by promoting ubiquitination in a mouse model of tauopathies, Acta Neuropathol., 2005, 110, 547–556 10.1007/s00401-005-1087-4Search in Google Scholar PubMed

[131] Engel T., Goñi-Oliver P., Lucas J.J., Avila J., Hernández F., Chronic lithium administration to FTDP-17 tau and GSK-3β overexpressing mice prevents tau hyperphosphorylation and neurofibrillary tangle formation, but pre-formed neurofibrillary tangles do not revert, J. Neurochem., 2006, 99, 1445–1455 10.1111/j.1471-4159.2006.04139.xSearch in Google Scholar PubMed

[132] Rockenstein E., Torrance M., Adame A., Mante M., Bar-on P., Rose J.B., et al., Neuroprotective effects of regulators of the glycogen synthase kinase-3β signaling pathway in a transgenic model of Alzheimer’s disease are associated with reduced amyloid precursor protein phosphorylation, J. Neurosci., 2007, 27, 1981–1991 10.1523/JNEUROSCI.4321-06.2007Search in Google Scholar PubMed PubMed Central

[133] Leroy K., Ando K., Héraud C., Yilmaz Z., Authelet M., Boeynaems J.M., et al., Lithium treatment arrests the development of neurofibrillary tangles in mutant tau transgenic mice with advanced neurofibrillary pathology, J. Alzheimers Dis., 2010, 19, 705–719 10.3233/JAD-2010-1276Search in Google Scholar PubMed

[134] Onishi T., Iwashita H., Uno Y., Kunitomo J., Saitoh M., Kimura E., et al., A novel glycogen synthase kinase-3 inhibitor 2-methyl-5-(3-{4-[(S)-methylsulfinyl]phenyl}-1-benzofuran-5-yl)-1, 3, 4-oxadiazole decreases tau phosphorylation and ameliorates cognitive deficits in a transgenic model of Alzheimer’s disease, J. Neurochem., 2011, 119, 1330–1340 10.1111/j.1471-4159.2011.07532.xSearch in Google Scholar PubMed

[135] Noh M.Y., Chun K., Kang B.Y., Kim H., Park J.S., Lee H.C., et al., Newly developed glycogen synthase kinase-3 (GSK-3) inhibitors protect neuronal cells death in amyloid-β induced cell model and in a transgenic mouse model of Alzheimer’s disease, Biochem. Biophys. Res. Commun., 2013, 435, 274–281 10.1016/j.bbrc.2013.04.065Search in Google Scholar PubMed