Skip to main content

Advertisement

SpringerLink
Log in

Klotho at the Edge of Alzheimer’s Disease and Senile Depression

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Klotho, encoded by the KL gene, is a single-pass transmembrane protein and a circulating factor that plays a key role in cellular metabolism and body homeostasis and has been associated with age-related diseases. Alterations of this protein seem to influence the development of serotonergic neurons and could play a role in major depression in the elderly. Pretreatment of neurons with Klotho protein can avoid neuronal injury related to the toxic amyloid-β and glutamate, centrally related to the pathogenesis of Alzheimer’s disease (AD), in order that Klotho protein could play a neuroprotective role in AD patients. Late-life depression, mild cognitive impairment, and dementia are different nosological entities but share common neurobiological facets and could represent a clinical continuum. Enhancement of Klotho levels in the early stages of the disease could represent a therapeutic strategy to prevent further deterioration and to ameliorate the outcome of elderly AD patients with or without major depression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Takizawa C, Thompson PL, van Walsem A, Faure C, Maier WC (2015) Epidemiological and economic burden of Alzheimer’s disease: a systematic literature review of data across Europe and the United States of America. J Alzheimers Dis 43(4):1271–1284. https://doi.org/10.3233/JAD-141134.

    Article  PubMed  Google Scholar 

  2. Naismith SL, Norrie LM, Mowszowski L, Hickie IB (2012) The neurobiology of depression in later-life: clinical, neuropsychological, neuroimaging and pathophysiological features. Prog Neurobiol 98(1):99–143. https://doi.org/10.1016/j.pneurobio.2012.05.009

    Article  PubMed  Google Scholar 

  3. Alexopoulos GS, Canuso CM, Gharabawi GM, Bossie CA, Greenspan A, Turkoz I, Reynolds C 3rd (2008) Placebo-controlled study of relapse prevention with risperidone augmentation in older patients with resistant depression. Am J Geriatr Psychiatry 16:21–30

    Article  Google Scholar 

  4. Panza F, Frisardi V, Capurso C, D'Introno A, Colacicco AM, Imbimbo BP, Santamato A, Vendemiale G et al (2010) Late-life depression, mild cognitive impairment, and dementia: possible continuum? Am J Geriatr Psychiatry 18(2):98–116. https://doi.org/10.1097/JGP.0b013e3181b0fa13

  5. Blazer DG (2003) Depression in late life: review and commentary. J Gerontol A Biol Sci Med Sci 58(3):249–265

    Article  Google Scholar 

  6. Luppa M, Luck T, König HH, Angermeyer MC, Riedel-Heller SG (2012) Natural course of depressive symptoms in late life. An 8-year population-based prospective study. J Affect Disord 142(1–3):166–171

    Article  Google Scholar 

  7. Büchtemann D, Luppa M, Bramesfeld A, Riedel-Heller S (2012) Incidence of late-life depression: a systematic review. J Affect Disord 142(1–3):172–179. https://doi.org/10.1016/j.jad.2012.05.010

    Article  PubMed  Google Scholar 

  8. Blazer D, Williams CD (1980) Epidemiology of dysphoria and depression in an elderly population. Am J Psychiatry 137(4):439–444

    Article  CAS  Google Scholar 

  9. Seripa D, Panza F, D'Onofrio G, Paroni G, Bizzarro A, Fontana A, Paris F, Cascavilla L et al (2013) The serotonin transporter gene locus in late-life major depressive disorder. Am J Geriatr Psychiatry 21(1):67–77. https://doi.org/10.1016/j.jagp.2012.10.012

  10. Ellison JM, Kyomen HH, Harper DG (2012) Depression in later life: an overview with treatment recommendations. Psychiatr Clin North Am 35(1):203–229. https://doi.org/10.1016/j.psc.2012.01.003

    Article  PubMed  Google Scholar 

  11. Katon WJ (2003) Clinical and health services relationships between major depression, depressive symptoms, and general medical illness. Biol Psychiatry 54(3):216–226

    Article  Google Scholar 

  12. Caraci F, Spampinato SF, Morgese MG, Tascedda F, Salluzzo MG, Giambirtone MC, Caruso G, Munafò A, Torrisi SA, Leggio GM, Trabace L, Nicoletti F, Drago F, Sortino MA, Copani A. (2018). Neurobiological links between depression and AD: the role of TGF-β1 signaling as a new pharmacological target. Pharmacol Res. doi: https://doi.org/10.1016/j.phrs.2018.02.007. pii: S1043-6618(17)31600–6

  13. Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M et al (1997) Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390(6655):45–51

  14. Kuang X, Chen YS, Wang LF, Li YJ, Liu K, Zhang MX, Li LJ, Chen C et al (2014) Klotho upregulation contributes to the neuroprotection of ligustilide in an Alzheimer’s disease mouse model. Neurobiol Aging 35(1):169–178. https://doi.org/10.1016/j.neurobiolaging.2013.07.019

  15. Semba RD, Moghekar AR, Hu J, Sun K, Turner R, Ferrucci L, O'Brien R (2014) Klotho in the cerebrospinal fluid of adults with and without Alzheimer’s disease. Neurosci Lett 558:37–40. https://doi.org/10.1016/j.neulet.2013.10.058

    Article  CAS  PubMed  Google Scholar 

  16. Dubal DB, Zhu L, Sanchez PE, Worden K, Broestl L, Johnson E, Ho K, Yu GQ et al (2015) Life extension factor klotho prevents mortality and enhances cognition in hAPP transgenic mice. J Neurosci 35(6):2358–2371. https://doi.org/10.1523/JNEUROSCI.5791-12.2015

  17. Yokoyama JS, Marx G, Brown JA, Bonham LW, Wang D, Coppola G, Seeley WW, Rosen HJ et al (2017) Systemic klotho is associated with KLOTHO variation and predicts intrinsic cortical connectivity in healthy human aging. Brain Imaging Behav 11(2):391–400. https://doi.org/10.1007/s11682-016-9598-2

  18. Arking DE, Krebsova A, Macek M Sr, Macek M Jr, Arking A, Mian IS, Fried L, Hamosh A et al (2002) Association of human aging with a functional variant of klotho. Proc Natl Acad Sci U S A 99(2):856–861

  19. Dubal DB, Yokoyama JS, Zhu L, Broestl L, Worden K, Wang D, Sturm VE, Kim D et al (2014) Life extension factor klotho enhances cognition. Cell Rep 7(4):1065–1076. https://doi.org/10.1016/j.celrep.2014.03.076

  20. Nagai T, Yamada K, Kim HC, Kim YS, Noda Y, Imura A, Nabeshima Y, Nabeshima T (2003) Cognition impairment in the genetic model of aging klotho gene mutant mice: a role of oxidative stress. FASEB J 17(1):50–52

    Article  CAS  Google Scholar 

  21. Deary IJ, Harris SE, Fox HC, Hayward C, Wright AF, Starr JM, Whalley LJ (2005) KLOTHO genotype and cognitive ability in childhood and old age in the same individuals. Neurosci Lett 378(1):22–27

    Article  CAS  Google Scholar 

  22. Arking DE, Becker DM, Yanek LR, Fallin D, Judge DP, Moy TF, Becker LC, Dietz HC (2003) KLOTHO allele status and the risk of early-onset occult coronary artery disease. Am J Hum Genet 72(5):1154–1161

    Article  CAS  Google Scholar 

  23. Arking DE, Atzmon G, Arking A, Barzilai N, Dietz HC (2005) Association between a functional variant of the KLOTHO gene and high-density lipoprotein cholesterol, blood pressure, stroke, and longevity. Circ Res 96(4):412–418

    Article  CAS  Google Scholar 

  24. Xu Y, Sun Z (2015) Molecular basis of klotho: from gene to function in aging. Endocr Rev 36(2):174–193. https://doi.org/10.1210/er.2013-1079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kim JH, Hwang KH, Park KS, Kong ID, Cha SK (2015) Biological role of anti-aging protein klotho. J Lifestyle Med 5(1):1–6. https://doi.org/10.15280/jlm.2015.5.1.1

    Article  PubMed  PubMed Central  Google Scholar 

  26. Lim K, Groen A, Molostvov G, Lu T, Lilley KS, Snead D, James S, Wilkinson IB et al (2015) α-Klotho expression in human tissues. J Clin Endocrinol Metab 100(10):E1308–E1318

  27. Hayashi Y, Ito M (2016) Klotho-related protein KLrP: structure and functions. Vitam Horm 101:1–16. https://doi.org/10.1016/bs.vh.2016.02.011.

    Article  CAS  PubMed  Google Scholar 

  28. Kuro-o M (2012) Klotho and βKlotho. Adv Exp Med Biol 728:25–40. https://doi.org/10.1007/978-1-4614-0887-1_2

    Article  CAS  PubMed  Google Scholar 

  29. Chen G, Liu Y, Goetz R, Fu L, Jayaraman S, Hu MC, Moe OW, Liang G et al (2018) α-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling. Nature 553(7689):461–466. https://doi.org/10.1038/nature25451

  30. Cararo-Lopes MM, Mazucanti CHY, Scavone C, Kawamoto EM, Berwick DC (2017) The relevance of α-KLOTHO to the central nervous system: some key questions. Ageing Res Rev 36:137–148. https://doi.org/10.1016/j.arr.2017.03.003

    Article  CAS  PubMed  Google Scholar 

  31. Massó A, Sánchez A, Gimenez-Llort L, Lizcano JM, Cañete M, García B, Torres-Lista V, Puig M et al (2015) Secreted and transmembrane αKlotho isoforms have different spatio-temporal profiles in the brain during aging and Alzheimer's disease progression. PLoS One 10(11):e0143623

  32. Mian IS (1998) Sequence, structural, functional, and phylogenetic analyses of three glycosidase families. Blood Cells Mol Dis 24:83–100

    CAS  PubMed  Google Scholar 

  33. Agostini M, Fasolato C (2016) When, where and how? Focus on neuronal calcium dysfunctions in Alzheimer’s disease. Cell Calcium 60(5):289–298. https://doi.org/10.1016/j.ceca.2016.06.008

    Article  CAS  PubMed  Google Scholar 

  34. Alzheimer’s Association Calcium Hypothesis Workgroup (2017) Calcium hypothesis of Alzheimer’s disease and brain aging: a framework for integrating new evidence into a comprehensive theory of pathogenesis. Alzheimers Dement 13(2):178–182.e17. https://doi.org/10.1016/j.jalz.2016.12.006

    Article  Google Scholar 

  35. Hurwitz S (1996) Homeostatic control of plasma calcium concentration. Crit Rev Biochem Mol Biol 31:41–100

    Article  CAS  Google Scholar 

  36. Jones G, Strugnell SA, DeLuca HF (1998) Current understanding of the molecular actions of Vitamin D. Physiol Rev 78:1193–1231

    Article  CAS  Google Scholar 

  37. Bushinsky DA, Monk RD (1998) Calcium. Lancet 352:306–311

    Article  CAS  Google Scholar 

  38. Shinki T, Shimada H, Wakino S, Anazawa H, Hayashi M, Saruta T, DeLuca HF, Suda T (1997) Cloning and expression of rat 25-hydroxyvitamin D3 1α-hydroxylase cDNA. Proc Natl Acad Sci U S A 94:12920–12925

    Article  CAS  Google Scholar 

  39. Shinki T, Ueno Y, DeLuca HF, Suda T (1999) Calcitonin is a major regulator for the expression of renal 25-hydroxyvitamin D3 1α-hydroxylase gene in normocalcemic rats. Proc Natl Acad Sci U S A 6:8253–8258

    Article  Google Scholar 

  40. Murayama A, Takeyama K, Kitanaka S, Kodera Y, Hosoya T, Kato S (1998) The promoter of the human 25-hydroxyvitamin D3 1α-hydroxylase gene confers positive and negative responsiveness to PTH, calcitonin, and 1α,25-(OH)2D3. Biochem Biophys Res Commun 249:11–16

    Article  CAS  Google Scholar 

  41. Iida K, Shinki T, Yamaguchi A, DeLuca HF, Kurokawa K, Suda T (1995) Possible role of Vitamin D receptors in regulating Vitamin D activation in the kidney. Proc Natl Acad Sci U S A 92:6112–6116

    Article  CAS  Google Scholar 

  42. Kato S (2000) The function of Vitamin D receptor in Vitamin D action. J Biochem 127:717–2267

    Article  CAS  Google Scholar 

  43. Yoshida T, Fujimori T, Nabeshima Y (2002) Mediation of unusually high concentrations of 1.25-hydroxyvitamin D3 in homozygous klotho mutant mice by increased expression of renal 1α-hydroxylase gene. Endocrinology 143:683–689

    Article  CAS  Google Scholar 

  44. Kumar R (1984) Metabolism of 1,25-hydroxyvitamin D3. Physiol Rev 64:478–504

    Article  CAS  Google Scholar 

  45. Zehner D, Hewison M (1999) The renal function of 25- hydroxivitamin D3 1α-hydroxylase. Mol Cell Endocrinol 151:213–220

    Article  Google Scholar 

  46. Nabeshima Y (2002) Klotho: a fundamental regulator of aging. Ageing research Rev 1:627–638

    Article  CAS  Google Scholar 

  47. Freude S, Hettich MM, Schumann C, Stöhr O, Koch L, Köhler C, Udelhoven M, Leeser U et al (2009) Neuronal IGF-1 resistance reduces Abeta accumulation and protects against premature death in a model of Alzheimer’s disease. FASEB J 23(10):3315–3324. https://doi.org/10.1096/fj.09-132043

  48. Zemva J, Schubert M (2014) The role of neuronal insulin/insulin-like growth factor-1 signaling for the pathogenesis of Alzheimer’s disease: possible therapeutic implications. CNS Neurol Disord Drug Targets 13(2):322–337

    Article  CAS  Google Scholar 

  49. Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, McGuinness OP, Chikuda H et al (2005) Suppression of aging in mice by the hormone Klotho. Science 309:1829–1833

  50. Guarente L, Kenyon C (2000) Genetic pathways that regulate ageing in model organisms. Nature 408(6809):255–262

    Article  CAS  Google Scholar 

  51. Kuro-o M (2001) Disease model: human aging. Trends Mol Med 7(4):179–181

    Article  CAS  Google Scholar 

  52. Jimenez C, Hernandez C, Pimentel B, Carrera AC (2002) The p85 regulatory subunit controls sequential activation of phosphoinositide 3-kinase by Tyr kinases and Ras. J Biol Chem 277(44):41556–41562

    Article  CAS  Google Scholar 

  53. Unger RH (2006) Klotho-induced insulin resistance: a blessing in disguise? Nat Med 12(1):56–57

    Article  CAS  Google Scholar 

  54. Boden G, Shulman GI (2002) Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and β-cell dysfunction. Eur J Clin Investig 32(Suppl. 3):14–23

    Article  CAS  Google Scholar 

  55. Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, Tran H, Ross SE et al (2004) Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303(5666):2011–2015

  56. Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado de Oliveira R, Leid M, McBurney MW et al (2004) Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ. Nature 429:771–776

  57. McGarry JD, Mannaerts GP, Foster DW (1997) A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis. J Clin Invest 60:265–270

    Article  Google Scholar 

  58. Staiger H, Keuper M, Berti L, Hrabe de Angelis M, Häring HU (2017) Fibroblast growth factor 21-metabolic role in mice and men. Endocr Rev 38(5):468–488. https://doi.org/10.1210/er.2017-00016

    Article  PubMed  Google Scholar 

  59. Suzuki M, Uehara Y, Motomura-Matsuzaka K, Oki J, Koyama Y, Kimura M, Asada M, Komi-Kuramochi A et al (2008) betaKlotho is required for fibroblast growth factor (FGF) 21 signaling through FGF receptor (FGFR) 1c and FGFR3c. Mol Endocrinol 22(4):1006–1014

  60. Bookout AL, de Groot MH, Owen BM, Lee S, Gautron L, Lawrence HL, Ding X, Elmquist JK et al (2013) FGF21 regulates metabolism and circadian behavior by acting on the nervous system. Nat Med 19(9):1147–1152

  61. Shardell M, Semba RD, Rosano C, Kalyani RR, Bandinelli S, Chia CW, Ferrucci L. (2015). Plasma klotho and cognitive decline in older adults: findings from the InCHIANTI study. J Gerontol A Biol Sci Med Sci. pii: glv140.

  62. Takahashi Y, Kuro-o M, Ishikawa F. (2000). Aging mechanisms. From the Academy. 97(23):12407–12408.

  63. Murray CJ, Lopez AD (1997) Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study. Lancet 349(9064):1498–1504

    Article  CAS  Google Scholar 

  64. Gold PW, Chrousos G, Kellner C, Post R, Roy A, Augerinos P, Schulte H, Oldfield E et al (1984) Psychiatric implications of basic and clinical studies with corticotropin-releasing factor. Am J Psychiatry 141:619–627

  65. Gold PW, Loriaux DL, Roy A, Kling MA, Calabrese JR, Kellner CH, Nieman LK, Post RM et al (1986) Responses to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing’s disease. Pathophysiologic and diagnostic implications. N Engl J Med 314:1329–1335

  66. Thakker-Varia S, Krol JJ, Nettleton J, Bilimoria PM, Bangasser DA, Shors TJ, Black IB, Alder J (2007) The neuropeptide VGF produces antidepressant-like behavioral effects and enhances proliferation in the hippocampus. J Neurosci 7:12156–12167

    Article  Google Scholar 

  67. Hunsberger JG, Newton SS, Bennett AH, Duman CH, Russell DS, Salton SR, Duman RS (2007) Antidepressant actions of the exercise-regulated gene VGF. Nat Med 13:1476–1482

    Article  CAS  Google Scholar 

  68. Nativio R, Donahue G, Berson A, Lan Y, Amlie-Wolf A, Tuzer F, Toledo JB, Gosai SJ et al (2018) Dysregulation of the epigenetic landscape of normal aging in Alzheimer’s disease. Nat Neurosci 21(4):497–505. https://doi.org/10.1038/s41593-018-0101-9

  69. Gold PW, Wong ML, Goldstein DS, Gold HK, Ronsaville DS, Esler M, Alesci S, Masood A et al (2005) Cardiac implications of increased arterial entry and reversible 24-h central and peripheral norepinephrine levels in melancholia. Proc Natl Acad Sci U S A 102:8303–8308

  70. Brandi LS, Santoro D, Natali A, Altomonte F, Baldi S, Frascerra S, Ferrannini E (1993) Insulin resistance of stress: sites and mechanisms. Clin Sci 85:525–535

    Article  CAS  Google Scholar 

  71. Wong ML, Kling MA, Munson PJ, Listwak S, Licinio J, Prolo P, Karp B, McCutcheon IE et al (2000) Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: relation to hypercortisolism and corticotropin-releasing hormone. Proc Natl Acad Sci U S A 97:325–330

  72. Kaplan MS, Hinds JW (1977) Neurogenesis in the adult rat: electron microscopic analysis of light radioautographs. Science 197:1092–1094

    Article  CAS  Google Scholar 

  73. Altman J, Das GD (1965) Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 124:319–335

    Article  CAS  Google Scholar 

  74. Salech F, Varela-Nallar L, Arredondo SB, Bustamante DB, Andaur GA, Cisneros R, Ponce DP, Ayala P, Inestrosa NC, Valdés JL, Behrens MI, Couve A. (2017) Local Klotho enhances neuronal progenitor proliferation in the adult hippocampus. J Gerontol A Biol Sci Med Sci. 30. doi: https://doi.org/10.1093/gerona/glx248.

  75. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J et al (2003) Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301:805–809

  76. Sahay A, Hen R (2007) Adult hippocampal neurogenesis in depression. Nat Neurosci 10:1110–1115

    Article  CAS  Google Scholar 

  77. Surget A, Saxe M, Leman S, Ibarguen-Vargas Y, Chalon S, Griebel G, Hen R, Belzung C (2008) Drug dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal. Biol Psychiatry 64:293–301

    Article  CAS  Google Scholar 

  78. Surget A, Tanti A, Leonardo ED, Laugeray A, Rainer Q, Touma C, Palme R, Griebel G et al (2011) Antidepressants recruit new neurons to improve stress response regulation. Mol Psychiatry 16:1177–1188

  79. Malberg JE, Eisch AJ, Nestler EJ, Duman RS (2000) Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 20:9104–9110

    Article  CAS  Google Scholar 

  80. Zhao C, Deng W, Gage FH (2008) Mechanisms and functional implications of adult neurogenesis. Cell 132:645–660

    Article  CAS  Google Scholar 

  81. Gold PW, Licinio J, Pavlatou MG (2013) Pathological parainflammation and endoplasmic reticulum stress in depression: potential translational targets through the CNS insulin, klotho and PPAR-γ systems. Mol Psychiatry 18(2):154–165. https://doi.org/10.1038/mp.2012.167

    Article  CAS  PubMed  Google Scholar 

  82. Chen CD, Podvin S, Gillespie E, Leeman SE, Abraham CR (2007) Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17. Proc Natl Acad Sci U S A 104:19796–19801

    Article  CAS  Google Scholar 

  83. Bloch L, Sineshchekova O, Reichenbach D, Reiss K, Saftig P, Kuro-o M (2009) Klotho is a substrate for α-, β- and γ-secretase. FEBS Lett 583:3221–3224

    Article  CAS  Google Scholar 

  84. Imura A, Iwano A, Tohyama O, Tsuji Y, Nozaki K, Hashimoto N (2004) Secreted Klotho protein in sera and CSF: implication for post-translational cleavage in release of Klotho protein from cell membrane. FEBS Lett 565:143–147

    Article  CAS  Google Scholar 

  85. Kuro-o M (2010) Klotho. Pflugers Arch 459:333–343

    Article  CAS  Google Scholar 

  86. Kuro-o M (2008) Klotho as a regulator of oxidative stress and senescence. Biol Chem 389:233–241

    Article  CAS  Google Scholar 

  87. Saito Y, Yamagishi T, Nakamura T, Ohyama Y, Aizawa H, Suga T, Matsumura Y, Masuda H et al (1998) Klotho protein protects against endothelial dysfunction. Biochem Biophys Res Commun 248:324–329

  88. Imura A, Tsuji Y, Murata M, Maeda R, Kubota K, Iwano A, Obuse C, Togashi K et al (2007) alpha-Klotho as a regulator of calcium homeostasis. Science 316:1615–1618

  89. de Groot T, Bindels RJ, Hoenderop JG (2008) TRPV5: an ingeniously controlled calcium channel. Kidney Int 74:1241–1246

    Article  Google Scholar 

  90. Li SA, Watanabe M, Yamada H, Nagai A, Kinuta M, Takei K (2004) Immunohistochemical localization of Klotho protein in brain, kidney, and reproductive organs of mice. Cell Struct Funct 29:91–99

    Article  CAS  Google Scholar 

  91. Zeldich E, Chen CD, Colvin TA, Bove-Fenderson EA, Liang J, Tucker Zhou TB, Harris DA, Abraham CR (2014) The neuroprotective effect of Klotho is mediated via regulation of members of the redox system. J Biol Chem 289(35):24700–24715

    Article  CAS  Google Scholar 

  92. Leon J, Moreno AJ, Garay BI, Chalkley RJ, Burlingame AL, Wang D, Dubal DB (2017) Peripheral elevation of a klotho fragment enhances brain function and resilience in young, aging, and α-synuclein transgenic mice. Cell Rep 20(6):1360–1371. https://doi.org/10.1016/j.celrep.2017.07.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Sato S, Kawamata Y, Takahashi A, Imai Y, Hanyu A, Okuma A, Takasugi M, Yamakoshi K et al (2015) Ablation of the p16(INK4a) tumour suppressor reverses ageing phenotypes of klotho mice. Nat Commun 6:7035. https://doi.org/10.1038/ncomms8035

  94. Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, Nabeshima Y (1998) Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochem Biophys Res Commun 242:626–630

    Article  CAS  Google Scholar 

  95. Shiraki-Iida T, Aizawa H, Matsumura Y, Sekine S, Iida A, Anazawa H, Nagai R, Kuro-o M et al (1998) Structure of the mouse klotho gene and its two transcripts encoding membrane and secreted protein. FEBS Lett 424:6–10

  96. Fukino K, Suzuki T, Saito Y, Shindo T, Amaki T, Kurabayashi M, Nagai R (2002) Regulation of angiogenesis by the aging suppressor gene klotho. Biochem Biophys Res Commun 293:332–337

    Article  CAS  Google Scholar 

  97. de Bruijn RF, Ikram MA (2014) Cardiovascular risk factors and future risk of Alzheimer’s disease. BMC Med 12:130. https://doi.org/10.1186/s12916-014-0130-5

    Article  PubMed  PubMed Central  Google Scholar 

  98. World Health Organization. http://www.who.int/mental_health/ management/ depression/wfmh_paper_depression_wmhd_2012.pdf. Accessed 3.4.2018

  99. Charney DS, Nemeroff CB, Lewis L, Laden SK, Gorman JM, Laska EM, Borenstein M, Bowden CL et al (2002) National Depressive and Manic-Depressive Association consensus statement on the use of placebo in clinical trials of mood disorders. Arch Gen Psychiatry 59:262–270

  100. Weissman MM, Bruce ML, Leaf PJ, Florio LP, Holzer CE (1991) Affective disorders. In: Robins LN, Regier DA (eds) Psychiatric disorders in America. The Free Press, New York, pp. 53–80

    Google Scholar 

  101. Wulsin LR, Evans JC, Vasan RS, Murabito JM, Kelly-Hayes M, Benjamin EJ (2005) Depressive symptoms, coronary heart disease, and overall mortality in the Framingham Heart Study. Psychosom Med 67:697–702

    Article  Google Scholar 

  102. Eaton WW, Armenian H, Gallo J, Pratt L, Ford DE (1996) Depression and risk for onset of type II diabetes: a prospective population-based study. Diabetes Care 19:1097–1102

    Article  CAS  Google Scholar 

  103. Penninx BW, Beekman AT, Honig A, Deeg DJ, Schoevers RA, van Eijk JT, van Tilburg W (2001) Depression and cardiac mortality: results from a community-based longitudinal study. Arch Gen Psychiatry 58:221–227

    Article  CAS  Google Scholar 

  104. Chang CK, Hayes RD, Perera G, Broadbent MT, Fernandes AC, Lee WE, Hotopf M, Stewart R (2011) Life expectancy at birth for people with serious mental illness and other major disorders from a secondary mental health care case register in London. PLoS One 6(5):e19590

    Article  CAS  Google Scholar 

  105. Harrington R (2002) Affective disorders. In: Rutter M, Taylor E (eds) Child and adolescent psychiatry, Fourth edn. Blackwell, Oxford, pp. 463–485

  106. Tamminga CA, Nemeroff CB, Blakely RD, Brady L, Carter CS, Davis KL, Dingledine R, Gorman JM et al (2002) Developing novel treatments for mood disorders: accelerating discovery. Biol Psychiatry 52:589–609

  107. Quintin P, Benkelfat C, Launay JM, Arnulf I, Pointereau-Bellenger A, Barbault S, Alvarez JC, Varoquaux O et al (2001) Clinical and neurochemical effect of acute tryptophan depletion in unaffected relatives of patients with bipolar affective disorder. Biol Psychiatry 50:184–190

  108. Smith KA, Fairburn CG, Cowen PJ (1997) Relapse of depression after rapid depletion of tryptophan. Lancet 349:915–919

    Article  CAS  Google Scholar 

  109. Bhagwagar Z, Rabiner EA, Sargent PA, Grasby PM, Cowen PJ (2004) Persistent reduction in brain serotonin1A receptor binding in recovered depressed men measured by positron emission tomography with [11C]WAY–100635. Mol Psychiatry 9:386–392

    Article  CAS  Google Scholar 

  110. Malison RT, Price LH, Berman R, van Dyck CH, Pelton GH, Carpenter L, Sanacora G, Owens MJ et al (1998) Reduced brain serotonin transporter availability in major depression as measured by [123I]–2 beta-carbomethoxy–3 beta-(4-iodophenyl) tropane and single photon emission computed tomography. Biol Psychiatry 44:1090–1098

  111. Cox GR, Callahan P, Churchill R, Hunot V, Merry SN, Parker AG, Hetrick SE (2012) Psychological therapies versus antidepressant medication, alone and in combination for depression in children and adolescents. Cochrane Database Syst Rev 11:CD008324

    PubMed  Google Scholar 

  112. Wilkinson P, Izmeth Z (2012) Continuation and maintenance treatments for depression in older people. Cochrane Database Syst Rev 11:CD006727

    PubMed  Google Scholar 

  113. Kraus C, Castrén E, Kasper S, Lanzenberger R (2017) Serotonin and neuroplasticity—links between molecular, functional and structural pathophysiology in depression. Neurosci Biobehav Rev 77:317–326. https://doi.org/10.1016/j.neubiorev.2017.03.007

    Article  CAS  PubMed  Google Scholar 

  114. Gałecki P, Mossakowska-Wójcik J, Talarowska M (2018) The anti-inflammatory mechanism of antidepressants—SSRIs, SNRIs. Prog Neuropsychopharmacol Biol Psychiatry 80(Pt C):291–294. https://doi.org/10.1016/j.pnpbp.2017.03.016

    Article  CAS  PubMed  Google Scholar 

  115. Mengel-From J, Soerensen M, Nygaard M, McGue M, Christensen K, Christiansen L. (2015). Genetic variants in KLOTHO associate with cognitive function in the oldest old group. J Gerontol A Biol Sci Med Sci. pii: glv163.

  116. Hao Q, Ding X, Gao L, Yang M, Dong B (2016) G-395A polymorphism in the promoter region of the KLOTHO gene associates with reduced cognitive impairment among the oldest old. Age (Dordr) 38(1):7. https://doi.org/10.1007/s11357-015-9869-7

    Article  Google Scholar 

  117. Paroni G, Seripa D, Fontana A, D'Onofrio G, Gravina C, Urbano M, Addante F, Lozupone M et al (2017) Klotho gene and selective serotonin reuptake inhibitors: response to treatment in late-life major depressive disorder. Mol Neurobiol 54(2):1340–1351. https://doi.org/10.1007/s12035-016-9711-y

  118. Wang Q, Yuan J, Yu Z, Lin L, Jiang Y, Cao Z, Zhuang P, Whalen MJ, Song B, Wang XJ, Li X, Lo EH, Xu Y, Wang X. (2017). FGF21 attenuates high-fat diet-induced cognitive impairment via metabolic regulation and anti-inflammation of obese mice. Mol Neurobiol. doi: https://doi.org/10.1007/s12035-017-0663-7.

  119. Codocedo JF, Ríos JA, Godoy JA, Inestrosa NC (2016) Are microRNAs the molecular link between metabolic syndrome and Alzheimer’s disease. Mol Neurobiol 53(4):2320–2338. https://doi.org/10.1007/s12035-015-9201-7

    Article  CAS  PubMed  Google Scholar 

  120. Kuriyama N, Ozaki E, Mizuno T, Ihara M, Mizuno S, Koyama T, Matsui D, Watanabe I et al (2018) Association between α-Klotho and deep white matter lesions in the brain: a pilot case control study using brain MRI. J Alzheimers Dis 61(1):145–155. https://doi.org/10.3233/JAD-170466

  121. Almeida OP, Morar B, Hankey GJ, Yeap BB, Golledge J, Jablensky A, Flicker L (2017) Longevity Klotho gene polymorphism and the risk of dementia in older men. Maturitas 101:1–5. https://doi.org/10.1016/j.maturitas.2017.04.005

    Article  CAS  PubMed  Google Scholar 

  122. Abraham CR, Mullen PC, Tucker-Zhou T, Chen CD, Zeldich E (2016) Klotho is a neuroprotective and cognition-enhancing protein. Vitam Horm 101:215–238. https://doi.org/10.1016/bs.vh.2016.02.004

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study was supported by the “5 × 1000” voluntary contribution and by the Italian Ministry of Health through IRCCS Scientific Institute and Regional General Hospital Casa Sollievo della Sofferenza, Opera di Padre Pio da Pietrelcina, San Giovanni Rotondo (FG), Italy (Research Program RC2015-2017, Linea n. 2 “Malattie complesse e terapie innovative” to DS and RC1603ME43, RC1703ME43, RC1803ME40 to GM).

Author information

Authors and Affiliations

  1. Department of Medical Sciences, Geriatrics Unit and Gerontology-Geriatrics Research Laboratory, IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza”, San Giovanni Rotondo, Italy

    Giulia Paroni, Francesco Panza, Antonio Greco & Davide Seripa

  2. Department of Medical Sciences, Division of Internal Medicine and Chronobiology Unit, IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza”, San Giovanni Rotondo, Italy

    Salvatore De Cosmo & Gianluigi Mazzoccoli

Authors
  1. Giulia Paroni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francesco Panza
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Salvatore De Cosmo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Antonio Greco
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Davide Seripa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gianluigi Mazzoccoli
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

GP and GM conceived and wrote the article. FP, SDC, AG, and DS critically reviewed the manuscript.

Corresponding author

Correspondence to Gianluigi Mazzoccoli.

Ethics declarations

Conflict of Interest Statement

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Paroni, G., Panza, F., De Cosmo, S. et al. Klotho at the Edge of Alzheimer’s Disease and Senile Depression. Mol Neurobiol 56, 1908–1920 (2019). https://doi.org/10.1007/s12035-018-1200-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-018-1200-z

Keywords

Search

Navigation