Is L-methionine a trigger factor for Alzheimer's-like neurodegeneration?: Changes in Aβ oligomers, tau phosphorylation, synaptic proteins, Wnt signaling and behavioral impairment in wild-type mice

Molecular Neurodegeneration

Volumn 10, Issue 1, 2015, Pages

  Tapia Rojas, Cheril ^a   Lindsay, Carolina B ^a   Montecinos Oliva, Carla ^a   Arrazola, Macarena S ^a   Retamales, Rocio M ^a   Bunout, Daniel ^b   Hirsch, Sandra ^b   Inestrosa, Nibaldo C ^a,c,d  

^a PONTIFICIA UNIVERSIDAD CATÓLICA DE CHILE   (Chile)

^b UNIVERSITY OF CHILE   (Chile)

^c UNIVERSITY OF NEW SOUTH WALES   (Australia)

^d UNIVERSIDAD DE MAGALLANES   (Chile)

Author keywords

Alzheimer's disease; Amyloid; L Methionine; Memory impairment; Tau

Indexed keywords

AMYLOID BETA PROTEIN; METHIONINE; PROTEIN; SYNAPTIC PROTEIN; TAU PROTEIN; UNCLASSIFIED DRUG; AMYLOID PRECURSOR PROTEIN;

ALZHEIMER LIKE NEURODEGENERATION; AMNESIA; ANIMAL TISSUE; ARTICLE; BEHAVIOR DISORDER; BRAIN FUNCTION; CONTROLLED STUDY; DIET; FEMALE; IN VIVO STUDY; INFLAMMATION; MEMORY DISORDER; MOUSE; NERVE DEGENERATION; NEUROTOXICITY; NONHUMAN; OXIDATIVE STRESS; PROTEIN PHOSPHORYLATION; WILD TYPE MOUSE; WNT SIGNALING PATHWAY; ALZHEIMER DISEASE; ANIMAL; ANIMAL BEHAVIOR; BRAIN; C57BL MOUSE; METABOLISM; NERVE CELL; PHOSPHORYLATION; PHYSIOLOGY;

ALZHEIMER DISEASE; AMYLOID BETA-PEPTIDES; AMYLOID BETA-PROTEIN PRECURSOR; ANIMALS; BEHAVIOR, ANIMAL; BRAIN; FEMALE; METHIONINE; MICE, INBRED C57BL; NEURONS; OXIDATIVE STRESS; PHOSPHORYLATION; TAU PROTEINS; WNT SIGNALING PATHWAY;

EID: 84947934653     PISSN: None     EISSN: 17501326     Source Type: Journal    
DOI: 10.1186/s13024-015-0057-0     Document Type: Article

References (105)

1. Orgeron ML, Stone KP, Wanders D, Cortez CC, van NT, Gettys TW. The impact of dietary methionine restriction on biomarkers of metabolic health. Prog Mol Biol Transl Sci. 2014;121:351-376.
2. Levine RL, Mosoni L, Berlett BS, Stadtman ER. Methionine residues as endogenous antioxidants in proteins. Proc Natl Acad Sci U S A. 1996;93:15036-15040.
3. Levine RL, Berlett BS, Moskovitz J, Mosoni L, Stadtman ER. Methionine residues may protect proteins from critical oxidative damage. Mech Ageing Dev. 1999;107:323-332.
4. Stadtman ER, Moskovitz J, Berlett BS, Levine RL. Cyclic oxidation and reduction of protein methionine residues is an important antioxidant mechanism. Mol Cell Biochem. 2002;234-235:3-9.
5. Stadtman ER, Moskovitz J, Levine RL. Oxidation of methionine residues of proteins: biological consequences. Antioxid Redox Signal. 2003;5(5):577-82.
6. Caso G, Garlick PJ. Control of muscle protein kinetics by acid-base balance. Curr Opin Clin Nutr Metab Care. 2005;8(1):73-6.
7. Mischoulon D, Fava M. Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence. Am J Clin Nutr. 2002;76(5):1158S-61.
8. Hardy ML, Coulter I, Morton SC, Favreau J, Venuturupalli S, Chiappelli F, et al. S-adenosyl-L-methionine for treatment of depression, osteoarthritis, and liver disease. Evid Rep Technol Assess (Summ). 2003:1-3.
9. Garlick PJ. Toxicity of methionine in humans. J Nutr. 2006;136(6 Suppl):1722S-5.
10. Toue S, Kodama R, Amao M, Kawamata Y, Kimura T, Sakai R. Screening of toxicity biomarkers for methionine excess in rats. J Nutr. 2006;136:1716S-1721S.
11. Koladiya RU, Jaggi AS, Singh N, Sharma BK. Ameliorative role of Atorvastatin and Pitavastatin in L-Methionine induced vascular dementia in rats. BMC Pharmacol. 2008;8:14.
12. Irwin MI, Hegsted DM. A conspectus of research on amino acid requirements of man. J Nutr. 1971;101(4):539-66.
13. Millward J. Amino acid requirements in adult man. Am J Clin Nutr. 1990;51(3):492-6.
14. Shea TB, Rogers E. Lifetime requirement of the methionine cycle for neuronal development and maintenance. Curr Opin Psychiatry. 2014;27(2):138-42. doi: 10.1097/YCO.0000000000000046.
15. Brosnan JT, Brosnan ME. The sulfur-containing amino acids: an overview. J Nutr. 2006;136(6 Suppl):1636S-40.
16. Lazzerini P, Capecchi P, Selvi E, Lorenzini S, Bisogno S, Galeazzi M, et al. Hyperhomocysteinemia, inflammation and autoimmunity. Autoimmun Rev 2007;7:503-509.
17. Boldyrev AA. Molecular mechanisms of homocysteine toxicity. Biochemistry (Mosc). 2009;74(6):589-98.
18. Hooshmand B, Polvikoski T, Kivipelto M, Tanskanen M, Myllykangas L, Erkinjuntti T, et al. Plasma homocysteine, Alzheimer and cerebrovascular pathology: a population-based autopsy study. Brain. 2013;136:2707-2716.
19. Ingenbleek Y, Kimura H. Nutritional essentiality of sulfur in health and disease. Nutr Rev. 2013;71(7):413-32.
20. Aune D, Ursin G, Veierod MB. Meat consumption and the risk of type 2 diabetes: a systematic review and meta-analysis of cohort studies. Diabetologia. 2009;52(11):2277-87.
21. Micha R, Wallace SK, Mozaffarian D. Red and processed meat consumption and risk of incident coronary heart disease, stroke, and diabetes mellitus: a systematic review and meta-analysis. Circulation. 2010;121(21):2271-83.
22. Nestoros JN, Ban TA, Lehmann HE. Transmethylation hypothesis of schizophrenia: methionine and nicotinic acid. Int Pharmacopsychiatry. 1977;12(4):215-46.
23. Cohen BM, Lipinski JF, Vuckovic A, Prosser E. Blood S-adenosyl-L-methionine levels in psychiatric disorders. Am J Psychiatry. 1982;139:229-231.
24. Smythies JR, Alarcon RD, Morere D, Monti JA, Steele M, Tolbert LC, et al. Abnormalities of one-carbon metabolism in psychiatric disorders: study of methionine adenosyltransferase kinetics and lipid composition of erythrocyte membranes. Biol Psychiatry. 1986;21:1391-1398.
25. Goren JL, Stoll AL, Damico KE, Sarmiento IA, Cohen BM. Bioavailability and lack of toxicity of S-adenosyl-L-methionine (SAMe) in humans. Pharmacotherapy. 2004;24:1501-1507.
26. Ringman JM, Coppola G. New genes and new insights from old genes: update on Alzheimer disease. Continuum (Minneap Minn). 2013;19(2 Dementia):358-71.
27. Stadtman ER, Van Remmen H, Richardson A, Wehr NB, Levine RL. Methionine oxidation and aging. Biochim Biophys Acta. 2005;1703:135-140.
28. Vuaden FC, Savio LE, Piato AL, Pereira TC, Vianna MR, Bogo MR, et al. Long-term methionine exposure induces memory impairment on inhibitory avoidance task and alters acetylcholinesterase activity and expression in zebrafish (Danio rerio). Neurochem Res. 2012;37:1545-1553.
29. Hrncic D, Rasic-Markovic A, Stojkovic T, Velimirovic M, Puskas N, Obrenovic R, et al. Hyperhomocysteinemia induced by methionine dietary nutritional overload modulates acetylcholinesterase activity in the rat brain. Mol Cell Biochem. 2014;396:99-105.
30. Velez-Carrasco W, Merkel M, Twiss CO, Smith JD. Dietary methionine effects on plasma homocysteine and HDL metabolism in mice. J Nutr Biochem. 2008;19:362-370.
31. Mucke L, Selkoe DJ. Neurotoxicity of Amyloid β-Protein: Synaptic and Network Dysfunction. Cold Spring Harb Perspect Med. 2012;2(7):a006338.
32. Zhang C, Tian Q, Wei W, Peng J, Liu GP, Zhou X, et al. Homocysteine induces tau phosphorylation by inactivating protein phosphatase 2A in rat hippocampus. Neurobiol Aging. 2008;29:1654-1665.
33. Loureiro S, Heimfarth L, Pelaez Pde L, Vanzin C, Viana L, Wyse A, et al. Homocysteine activates calcium-mediated cell signaling mechanisms targeting the cytoskeleton in rat hippocampus. Int J Dev Neurosci. 2008:447-455.
34. McCampbell A, Wessner K, Marlatt M, Wolffe C, Toolan D, Podtelezhnikov A, et al. Induction of Alzheimer's-like changes in brain of mice expressing mutant APP fed excess methionine. J Neurochem. 2011;116:82-92.
35. Sengupta A, Kabat J, Novak M, Wu Q, Grundke-Iqbal I, Iqbal K. Phosphorylation of tau at both Thr 231 and Ser 262 is required for maximal inhibition of its binding to microtubules. Arch Biochem Biophys. 1998;357:299-309.
36. Zhang C, Wei W, Liu Y, Peng J, Tian Q, Liu G, et al. Hyperhomocysteinemia increases beta-amyloid by enhancing expression of gamma-secretase and phosphorylation of amyloid precursor protein in rat brain. Am J Pathol. 2009;174:1481-1491.
37. Mufson EJ, He B, Nadeem M, Perez SE, Counts SE, Leurgans S, et al. Hippocampal proNGF signaling pathways and beta-amyloid levels in mild cognitive impairment and Alzheimer disease. J Neuropathol Exp Neurol. 2012;71:1018-1029.
38. Teich AF, Patel M, Arancio O. A reliable way to detect endogenous murine beta-amyloid. PLoS One. 2013;8(2):e55647.
39. Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, et al. A specific amyloid-beta protein assembly in the brain impairs memory. Nature. 2006;440:352-357.
40. Agbas A, Moskovitz J. The Role of Methionine Oxidation/Reduction in the Regulation of Immune Response. Curr Signal Transduct Ther. 2009;4(1):46-50.
41. Grimble RF. The effects of sulfur amino acid intake on immune function in humans. J Nutr. 2006;136(6 Suppl):1660S-5.
42. Perna A, Ingrosso D, De Santo N. Homocysteine and oxidative stress. Amino Acids. 2003;25(3-4):409-17.
43. McCully K. Chemical pathology of homocysteine. IV. Excitotoxicity, oxidative stress, endothelial dysfunction, and inflammation. Ann Clin Lab Sci. 2009;39(3):219-32.
44. Makhro A, Mashkina A, Solenaya O, Trunova O, Kozina L, Arutyunian A, et al. Prenatal hyperhomocysteinemia as a model of oxidative stress of the brain. Bull Exp Biol Med. 2008;146:33-35.
45. Glantz LA, Lewis DA. Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Psychiatry. 2000;57(1):65-73.
46. Grayson DR, Chen Y, Dong E, Kundakovic M, Guidotti A. From trans-methylation to cytosine methylation: evolution of the methylation hypothesis of schizophrenia. Epigenetics. 2009;4:144-149.
47. Tueting P, Davis JM, Veldic M, Pibiri F, Kadriu B, Guidotti A, et al. L-methionine decreases dendritic spine density in mouse frontal cortex. Neuroreport. 2010;21:543-548.
48. Mukaetova-Ladinska E, Hurt J, Honer WG, Harrington CR, Wischik CM. Loss of synaptic but not cytoskeletal proteins in the cerebellum of chronic schizophrenics. Neurosci Lett. 2002;317:161-165.
49. Inestrosa NC, Tapia-Rojas C, Griffith TN, Carvajal FJ, Benito MJ, Rivera-Dictter A, et al. Tetrahydrohyperforin prevents cognitive deficit, Aβ deposition, tau phosphorylation and synaptotoxicity in the APPswe/PSEN1ΔE9 model of Alzheimer's disease: a possible effect on APP processing. Translational Psychiatry. 2011;1:9.
50. Toledo EM, Inestrosa NC. Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1DeltaE9 mouse model of Alzheimer's disease. Mol Psychiatry. 2010;15(3):272-85. 228.
51. Yatsugi S, Yamamoto T, Ohno M, Ueki S. Effect of S-adenosyl-L-methionine on impairment of working memory induced in rats by cerebral ischemia and scopolamine. Eur J Pharmacol. 1989;166:231-239.
52. Oulhaj A, Refsum H, Beaumont H, Williams J, King E, Jacoby R, et al. Homocysteine as a predictor of cognitive decline in Alzheimer's disease. Int J Geriatr Psychiatry. 2010;25:82-90.
53. Inestrosa NC, Arenas E. Emerging roles of Wnts in the adult nervous system. Nat Rev Neurosci. 2010;11(2):77-86.
54. Rosso S, Inestrosa N. WNT signaling in neuronal maturation and synaptogenesis. Front Cell Neurosci. 2013;7:103.
55. Inestrosa NC, Varela-Nallar L, Grabowski CP, Colombres M. Synaptotoxicity in Alzheimer's disease: the Wnt signaling pathway as a molecular target. IUBMB Life. 2007;59:316-321.
56. Inestrosa NC, Toledo EM. The role of Wnt signaling in neuronal dysfunction in Alzheimer's Disease. Mol Neurodegener. 2008;3:9.
57. Cerpa W, Toledo EM, Varela-Nallar L, Inestrosa NC. The role of Wnt signaling in neuroprotection. Drug News Perspect. 2009;22:579-591.
58. Fortress AM, Schram SL, Tuscher JJ, Frick KM. Canonical Wnt signaling is necessary for object recognition memory consolidation. J Neurosci. 2013;33:12619-12626.
59. Arrazola MS, Varela-Nallar L, Colombres M, Toledo EM, Cruzat F, Pavez L, et al. Calcium/calmodulin-dependent protein kinase type IV is a target gene of the Wnt/beta-catenin signaling pathway. J Cell Physiol. 2009;221:658-667.
60. Nusse R, Varmus H. Three decades of Wnts: a personal perspective on how a scientific field developed. EMBO J. 2012;31(12):2670-84.
61. Hodar C, Assar R, Colombres M, Aravena A, Pavez L, Gonzalez M, et al. Genome-wide identification of new Wnt/beta-catenin target genes in the human genome using CART method. BMC Genomics. 2010;11:348.
62. Hardy J, Selkoe D. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002;297(5580):353-6.
63. Zheng-Fischhofer Q, Biernat J, Mandelkow EM, Illenberger S, Godemann R, Mandelkow E. Sequential phosphorylation of Tau by glycogen synthase kinase-3beta and protein kinase A at Thr212 and Ser214 generates the Alzheimer-specific epitope of antibody AT100 and requires a paired-helical-filament-like conformation. Eur J Biochem. 1998;252:542-552.
64. Lesné S, Sherman M, Grant M, Kuskowski M, Schneider J, Bennett D, et al. Brain amyloid-β oligomers in ageing and Alzheimer's disease. Brain. 2013;136:1383-1398.
65. Reyes AE, Chacon MA, Dinamarca MC, Cerpa W, Morgan C, Inestrosa NC. Acetylcholinesterase-Abeta complexes are more toxic than Abeta fibrils in rat hippocampus: effect on rat beta-amyloid aggregation, laminin expression, reactive astrocytosis, and neuronal cell loss. Am J Pathol. 2004;164:2163-2174.
66. Nakamura T, Tu S, Akhtar M, Sunico C, Okamoto S, Lipton S. Aberrant protein s-nitrosylation in neurodegenerative diseases. Neuron. 2013;78:596-614.
67. Foster MW, McMahon TJ, Stamler JS. S-nitrosylation in health and disease. Trends Mol Med. 2003;9(4):160-8.
68. Foster MW, Hess DT, Stamler JS. Protein S-nitrosylation in health and disease: a current perspective. Trends Mol Med. 2009;15(9):391-404.
69. Gubandru M, Margina D, Tsitsimpikou C, Goutzourelas N, Tsarouhas K, Ilie M, et al. Alzheimer's disease treated patients showed different patterns for oxidative stress and inflammation markers. Food Chem Toxicol. 2013;S0278-6915:00468-00467.
70. Vargas JY, Fuenzalida M, Inestrosa NC. In vivo Activation of Wnt Signaling Pathway Enhances Cognitive Function of Adult Mice and Reverses Cognitive Deficits in an Alzheimer's Disease Model. J Neurosci. 2014;34(6):2191-202.
71. Morris RG. Episodic-like memory in animals: psychological criteria, neural mechanisms and the value of episodic-like tasks to investigate animal models of neurodegenerative disease. Philos Trans R Soc Lond B Biol Sci. 2001;356(1413):1453-65.
72. Zhuo JM, Portugal GS, Kruger WD, Wang H, Gould TJ, Pratico D. Diet-induced hyperhomocysteinemia increases amyloid-beta formation and deposition in a mouse model of Alzheimer's disease. Curr Alzheimer Res. 2010;7:140-149.
73. Miller AL. The methionine-homocysteine cycle and its effects on cognitive diseases. Altern Med Rev. 2003;8(1):7-19.
74. Troen AM, Lutgens E, Smith DE, Rosenberg IH, Selhub J. The atherogenic effect of excess methionine intake. Proc Natl Acad Sci U S A. 2003;100:15089-15094.
75. Selley ML, Close DR, Stern SE. The effect of increased concentrations of homocysteine on the concentration of (E)-4-hydroxy-2-nonenal in the plasma and cerebrospinal fluid of patients with Alzheimer's disease. Neurobiol Aging. 2002;23(3):383-8.
76. Nilsson K, Gustafson L, Hultberg B. Relation between plasma homocysteine and Alzheimer's disease. Dement Geriatr Cogn Disord. 2002;14(1):7-12.
77. Topal G, Brunet A, Millanvoye E, Boucher JL, Rendu F, Devynck MA, et al. Homocysteine induces oxidative stress by uncoupling of NO synthase activity through reduction of tetrahydrobiopterin. Free Radic Biol Med. 2004;36:1532-1541.
78. Sai X, Kawamura Y, Kokame K, Yamaguchi H, Shiraishi H, Suzuki R, et al. Endoplasmic reticulum stress-inducible protein, Herp, enhances presenilin-mediated generation of amyloid beta-protein. J Biol Chem. 2002;277:12915-12920.
79. Ho P, Ortiz D, Rogers E, Shea T. Multiple aspects of homocysteine neurotoxicity: glutamate excitotoxicity, kinase hyperactivation and DNA damage. J Neurosci Res. 2002;70:694-702.
80. Fuso A, Nicolia V, Cavallaro R, Ricceri L, D'Anselmi F, Coluccia P, et al. B-vitamin deprivation induces hyperhomocysteinemia and brain S-adenosylhomocysteine, depletes brain S-adenosylmethionine, and enhances PS1 and BACE expression and amyloid-beta deposition in mice. Mol Cell Neurosci. 2008;37:731-746.
81. Pacheco-Quinto J, Rodriguez de Turco E, DeRosa S, Howard A, Cruz-Sanchez F, Sambamurti K, et al. Hyperhomocysteinemic Alzheimer's mouse model of amyloidosis shows increased brain amyloid beta peptide levels. Neurobiol Dis. 2006;22:651-656.
82. James SJ, Melnyk S, Pogribna M, Pogribny IP, Caudill MA. Elevation in S-adenosylhomocysteine and DNA hypomethylation: potential epigenetic mechanism for homocysteine-related pathology. J Nutr. 2002;132:2361S-2366S.
83. Ho P, Collins S, Dhitavat S, Ortiz D, Ashline D, Rogers E, et al. Homocysteine potentiates beta-amyloid neurotoxicity: role of oxidative stress. J Neurochem. 2001;78:249-253.
84. Sontag E, Nunbhakdi-Craig V, Sontag J, Diaz-Arrastia R, Ogris E, Dayal S, et al. Protein phosphatase 2A methyltransferase links homocysteine metabolism with tau and amyloid precursor protein regulation. J Neurosci. 2007;27:2751-2759.
85. Lipton S, Kim W, Choi Y, Kumar S, D'Emilia D, Rayudu P, et al. Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. Proc Natl Acad Sci U S A. 1997;94:5923-5928.
86. De Ferrari GV, Chacon MA, Barria MI, Garrido JL, Godoy JA, Olivares G, et al. Activation of Wnt signaling rescues neurodegeneration and behavioral impairments induced by beta-amyloid fibrils. Mol Psychiatry. 2003;8:195-208.
87. Caricasole A, Copani A, Caraci F, Aronica E, Rozemuller AJ, Caruso A, et al. Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer's brain. J Neurosci. 2004;24:6021-6027.
88. Killick R, Ribe E, Al-Shawi R, Malik B, Hooper C, Fernandes C, et al. Clusterin regulates β-amyloid toxicity via Dickkopf-1-driven induction of the wnt-PCP-JNK pathway. Mol Psychiatry 2012. doi: 10.1038/mp.2012.163.
89. Zhang Z, Hartmann H, Do VM, Abramowski D, Sturchler-Pierrat C, Staufenbiel M, et al. Destabilization of beta-catenin by mutations in presenilin-1 potentiates neuronal apoptosis. Nature. 1998;395:698-702.
90. Alvarez AR, Godoy JA, Mullendorff K, Olivares GH, Bronfman M, Inestrosa NC. Wnt-3a overcomes beta-amyloid toxicity in rat hippocampal neurons. Exp Cell Res. 2004;297:186-196.
91. Purro SA, Dickins EM, Salinas PC. The secreted Wnt antagonist Dickkopf-1 is required for amyloid beta-mediated synaptic loss. J Neurosci. 2012;32(10):3492-8.
92. Caruso A, Motolese M, Iacovelli L, Caraci F, Copani A, Nicoletti F, et al. Inhibition of the canonical Wnt signaling pathway by apolipoprotein E4 in PC12 cells. J Neurochem. 2006;98:364-371.
93. De Ferrari G, Papassotiropoulos A, Biechele T, Wavrant De-Vrieze F, Avila M, Major M, et al. Common genetic variation within the low-density lipoprotein receptor-related protein 6 and late-onset Alzheimer's disease. Proc Natl Acad Sci U S A. 2007;104:9434-9439.
94. Liu CC, Tsai CW, Deak F, Rogers J, Penuliar M, Sung YM, et al. Deficiency in LRP6-mediated Wnt signaling contributes to synaptic abnormalities and amyloid pathology in Alzheimer's disease. Neuron. 2014;84:63-77.
95. Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet. 2009;41:1088-1093.
96. Inestrosa NC, Varela-Nallar L. Wnt signaling in the nervous system and in Alzheimer's disease. J Mol Cell Biol. 2014;6:64-74.
97. Inestrosa NC, Varela-Nallar L. Wnt signalling in neuronal differentiation and development. Cell Tissue Res. 2015;359:215-223.
98. Chen J, Park CS, Tang SJ. Activity-dependent synaptic Wnt release regulates hippocampal long term potentiation. J Biol Chem. 2006;281:11910-11916.
99. Tabatadze N, Tomas C, McGonigal R, Lin B, Schook A, Routtenberg A. Wnt transmembrane signaling and long-term spatial memory. Hippocampus. 2012;22:1228-1241.
100. Cerpa W, Godoy JA, Alfaro I, Farias GG, Metcalfe MJ, Fuentealba R, et al. Wnt-7a modulates the synaptic vesicle cycle and synaptic transmission in hippocampal neurons. J Biol Chem. 2008;283:5918-5927.
101. De Ferrari GV, Inestrosa NC. Wnt signaling function in Alzheimer's disease. Brain Res Brain Res Rev. 2000;33:1-12.
102. Carvajal F, Zolezzi J, Tapia-Rojas C, Godoy J, Inestrosa N. Tetrahydrohyperforin decreases cholinergic markers associated with amyloid-β plaques, 4-hydroxynonenal formation, and caspase-3 activation in AβPP/PS1 mice. J Alzheimers Dis. 2013;36:99-118.
103. Cancino GI, Toledo EM, Leal NR, Hernandez DE, Yevenes LF, Inestrosa NC, et al. STI571 prevents apoptosis, tau phosphorylation and behavioural impairments induced by Alzheimer's beta-amyloid deposits. Brain. 2008;131:2425-2442.
104. Varela-Nallar L, Grabowski CP, Alfaro IE, Alvarez AR, Inestrosa NC. Role of the Wnt receptor Frizzled-1 in presynaptic differentiation and function. Neural Dev. 2009;4:41.
105. Inestrosa N, Carvajal F, Zolezzi J, Tapia-Rojas C, Serrano F, Karmelic D, et al. Peroxisome proliferators reduce spatial memory impairment, synaptic failure, and neurodegeneration in brains of a double transgenic mice model of Alzheimer's disease. J Alzheimers Dis. 2013;33:941-959.