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Age-related changes of calcineurin and Akt1/protein kinase Bα (Akt1/PKBα) immunoreactivity in the mouse hippocampal CA1 sector: an immunohistochemical study

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Abstract

We investigated the age-related alterations of calcineurin and Akt1/protein kinase Bα (Akt1/PKBα) immunoreactivity in the mouse hippocampal CA1 sector using immunohistochemistry. Calcineurin and Akt1/PKBα immunoreactivity was measured in 2-, 8-, 18-, 40–42- and 50–59-weeks-old animals. Diffuse calcineurin immunoreactivity was evident in pyramidal neurons of the hippocampal CA1 sector of 8-weeks-old mice. Densities of calcineurin immunoreactivity were lowered significantly in the hippocampal CA1 neurons of 2-weeks-old mice. In contrast, densities of calcineurin immunoreactivity were unchanged in the hippocampal CA1 neurons up to 40–42-weeks-old mice. However, densities of calcineurin immunoreactivity were increased significantly in the dendrites and plasma membranes of the hippocampal CA1 neurons of 50–59-weeks-old mice compared to 8-weeks old animals. Akt1/PKBα immunoreactivity was slightly detectable in the hippocampal CA1 sector of 8-weeks-old mice. A weak Akt1/PKBα immunoreactivity was found in cytoplasm of the hippocampal CA1 neurons and glial cells. Densities of Akt1/PKBα immunoreactivity were unchanged in the hippocampal CA1 neurons and glial cells of 2-weeks-old mice. In contrast, densities of Akt1/PKBα immunoreactivity were increased significantly in cytoplasm of neurons and glial cells of the hippocampal CA1 sector from 40–42 to 50–59 weeks after birth. The present study indicates that densities of calcineurin immunoreactivity and number of Akt1/PKBα immunoreactive cells were increased significantly in the hippocampal CA1 sector during aging processes. Our study also demonstrates that the activation of Akt1/PKBα signaling pathway may act defense mechanism against the neuronal dysfunction of the hippocampal CA1 sector caused by the activation of calcineurin signaling pathway during aging processes. These findings suggest that the calcineurin and Akt1/PKBα signaling pathway may be important targets for the development of novel therapeutic strategies for protection against age-related neurodegeneration.

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References

  • Araki T, Kato H, Kanai Y, Kogure K (1993) Postischemic changes of intracellular second messengers in the gerbil brain after long-term survival: an autoradiographic study. Neuroscience 53:829–836

    Article  PubMed  CAS  Google Scholar 

  • Barnes CA (1979) Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat. J Comp Physiol Psychol 93:74–104

    Article  PubMed  CAS  Google Scholar 

  • Barnes CA (1988) Aging and the physiology of spatial memory. Neurobiol Aging 9:563–568

    Article  PubMed  CAS  Google Scholar 

  • Bito H, Deisseroth K, Tsien RW (1996) CREB phosphorylation and dephosphorylation: a Ca2+- and stimulus duration-dependent switch for hippocampal gene expression. Cell 87:1203–1214

    Article  PubMed  CAS  Google Scholar 

  • Brunet A, Datta SR, Greenberg ME (2001) Transcription-dependent and -independent control of neuronal survival by the PI3K–Akt signaling pathway. Curr Opin Neurobiol 11:297–305

    Article  PubMed  CAS  Google Scholar 

  • Chan TO, Rittenhouse SE, Tsichlis PN (1999) AKT/PKB and other D3 phosphoinositide-regulated kinases:kinase activation by phosphoinositide-dependent phosphorylation. Annu Rev Biochem 68:965–1014

    Article  PubMed  CAS  Google Scholar 

  • Chen WS, Xu PZ, Gottlob K, Chen ML, Sokol K, Shiyanova T, Roninson I, Weng W, Suzuki R, Tobe K, Kadowaki T, Hay N (2001) Growth retardation and increased apoptosis in mice with homozygous disruption of the akt1 gene. Genes Dev 15:2203–2208

    Article  PubMed  CAS  Google Scholar 

  • Cho H, Thorvaldsen JL, Chu Q, Feng F, Birnbaum MJ (2001) Akt1/PKBα is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J Biol Chem 276:38349–38352

    Article  PubMed  CAS  Google Scholar 

  • Coffer PJ, Woodgett JR (1991) Molecular cloning and characterization of a novel putative protein-serine kinase related to the cAMP-dependent and protein kinase C families. Eur J Biochem 201:475–481

    Article  PubMed  CAS  Google Scholar 

  • Crabtree GR, Olson EN (2002) NFAT signaling: choreographing the social lives of cells. Cell [Suppl] 109:S67–S79

    Article  CAS  Google Scholar 

  • Dawson TM, Steiner JP, Lyons WE, Fotuhi M, Blue M, Snyder SH (1994) The immunophilins, FK506 binding protein and cyclophilin, are discretely localized in the brain: relationship to calcineurin. Neuroscience 62:569–580

    Article  PubMed  CAS  Google Scholar 

  • DeToledo-Morrell L, Geinisman Y, Morrell F (1988) Age-dependent alterations in hippocampal synaptic plasticity: relation to memory disorders. Neurobiol Aging 9:581–590

    Article  PubMed  CAS  Google Scholar 

  • Disterhoft JF, Moyer JR Jr, Thompson LT (1994) The calcium rationale in aging and Alzheimer’s disease. Evidence from an animal model of normal aging. Ann NY Acad Sci 747:382–406

    Article  PubMed  CAS  Google Scholar 

  • Dudek H, Datta SR, Franke TF, Birnbaum MJ, Yao R, Cooper GM, Segal RA, Kaplan DR, Greenberg ME (1997) Regulation of neuronal survival by the serine–threonine protein kinase Akt. Science 275:661–665

    Article  PubMed  CAS  Google Scholar 

  • Easton RM, Cho H, Roovers K, Shineman DW, Mizrahi M, Forman MS, Lee VMY, Szabolcs M, de Jong R, Oltersdorf T, Ludwig T, Efstratiadis A, Birnbaum MJ (2005) Role for Akt3/protein kinase Bg in attainment of normal brain size. Moll Cell Biol 25:1869–1878

    Article  CAS  Google Scholar 

  • Eichenbaum H (2001) The hippocampus and declarative memory: cognitive mechanisms and neural codes. Behav Brain Res 127:199–207

    Article  PubMed  CAS  Google Scholar 

  • Eves EM, Xiong W, Bellacosa A, Kennedy SG, Tsichlis PN, Rosner MR, Hay N (1998) Akt, a target of phosphatidylinositol 3-kinase, inhibits apoptosis in a differentiating neuronal cell line. Mol Cell Biol 18:2143–2152

    PubMed  CAS  Google Scholar 

  • Foster TC (1999) Involvement of hippocampal synaptic plasticity in age-related memory decline. Brain Res Rev 30:236–249

    Article  PubMed  CAS  Google Scholar 

  • Foster TC, Norris CM (1997) Age-associated changes in Ca2+-dependent processes: relation to hippocampal synaptic plasticity. Hippocampus 7:602–612

    Article  PubMed  CAS  Google Scholar 

  • Foster TC, Sharrow KM, Masse JR, Norris CM, Kumar A (2001) Calcineurin links Ca2+ dysregulation with brain aging. J Neurosci 21:4066–4073

    PubMed  CAS  Google Scholar 

  • Gallagher M, Nicolle MM (1993) Animal models of normal aging: relationship between cognitive decline and markers in hippocampal circuitry. Behav Brain Res 57:155–162

    Article  PubMed  CAS  Google Scholar 

  • Garofalo RS, Orena SJ, Rafidi K, Torchia AJ, Stock JL, Hildebrandt AL, Coskran T, Black SC, Brees DJ, Wicks JR, McNeish JD, Coleman KG (2003) Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKBb. J Clin Invest 112:197–208

    PubMed  CAS  Google Scholar 

  • Geinisman Y, Toledo-Morrell L, Morrell F (1986) Loss of perforated synapses in the dentate gyrus: morphological substrate of memory deficit in aged rats. Proc Natl Acad Sci USA 83:3027–3031

    Article  PubMed  CAS  Google Scholar 

  • Goto S, Matsuoka Y, Mihara Y, Inoue N, Miyamoto E (1986) The distribution of calcineurin in rat brain by light and electron microscope immunohistochemistry and enzyme-immunoassay. Brain Res 397:161–172

    Article  PubMed  CAS  Google Scholar 

  • Hayakawa N, Kato H, Araki T (2007) Age-related changes of astrocytes, oligodendrocytes and microglia in the mouse hippocampal CA1 sector. Mech Ageing Dev 128:311–316

    Article  PubMed  CAS  Google Scholar 

  • Himeda T, Mizuno K, Kato H, Araki T (2006) Effects of age on immunohistochemical changes in the mouse hippocampus. Mech Ageing Dev 126:673–677

    Article  CAS  Google Scholar 

  • Homburger F, Russfield AB, Weisburger JH, Lim S, Chak SP, Weisburger EK (1975) Aging changes in CD-1 HaM/ICR mice reared under standard laboratory conditions. J Natl Cancer Inst 55:37–45

    PubMed  CAS  Google Scholar 

  • Kincaid RL, Balaban CD, Billingsley ML (1987) Differential localization of calmodulin-dependent enzymes in rat brain: evidence for selective expression of cyclic nucleotide phosphodiesterase in specific neurons. Proc Natl Acad Sci USA 84:1118–1122

    Article  PubMed  CAS  Google Scholar 

  • Kirino T (1982) Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res 239:57–69

    Article  PubMed  CAS  Google Scholar 

  • Klee CB, Crouch TH, Krinks MH (1979) Calcineurin: a calcium- and calmodulin-binding protein of the nervous system. Proc Natl Acad Sci USA 76:6270–6273

    Article  PubMed  CAS  Google Scholar 

  • Lai WS, Xu B, Westphal KGC, Olivier B, Pavlidis P, Karayiorgou M, Gogos JA (2006) Akt1 deficiency affects neuronal morphology and predisposes to abnormalities in prefrontal cortex functioning. Proc Natl Acad Sci USA 103:16906–16911

    Article  PubMed  CAS  Google Scholar 

  • Landfield PW (1988) Hippocampal neurobiological mechanisms of age-related memory dysfunction. Neurobiol Aging 9:571–579

    Article  PubMed  CAS  Google Scholar 

  • Malleret G, Haditsch U, Genoux D, Jones MW, Bliss TV, Vanhoose AM, Weitlauf C, Kandel ER, Winder DG, Mansuy IM (2001) Inducible and reversible enhancement of learning, memory, and long-term potentiation by genetic inhibition of calcineurin. Cell 104:675–686

    PubMed  CAS  Google Scholar 

  • Manning BD, Cantley LC (2007) Akt/PKB signaling: navigating downstream. Cell 129:1261–1274

    Article  PubMed  CAS  Google Scholar 

  • Mansuy IM, Mayford M, Jacob B, Kandel ER, Bach ME (1998) Restricted and regulated overexpression reveals calcineurin as a key component in the transition from short-term to long-term memory. Cell 92:39–49

    Article  PubMed  CAS  Google Scholar 

  • Mattson MP, LaFerla FM, Chan SL, Leissring MA, Shepel PN, Geiger JD (2000) Calcium signaling in the ER: its role in neuronal plasticity and neurodegenerative disorders. Trends Neurosci 23:222–229

    Article  PubMed  CAS  Google Scholar 

  • Mesulam MM (1999) Neuroplasticity failure in Alzheimer’s disease: bridging the gap between plaques and tangles. Neuron 24:521–529

    Article  PubMed  CAS  Google Scholar 

  • Miller DB, O’Callaghan JP (2005) Aging, stress and the hippocampus. Ageing Res Reviews 4:123–140

    Article  CAS  Google Scholar 

  • Ouyang YB, Tan Y, Comb M, Liu CL, Martone ME, Siesjo BK, Hu BR (1999) Survival- and death-promoting events after transient cerebral ischemia: phophorylation of Ark, release of cytochrome c and activation of caspase-like proteases. J Cereb Blood Flow Metab 19:1126–1135

    Article  PubMed  CAS  Google Scholar 

  • Pulsinelli WA, Brierley JB, Plum F (1982) Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann Neurol 11:491–498

    Article  PubMed  CAS  Google Scholar 

  • Salinas M, Lopez-Valdaliso R, Martin D, Alvarez A, Cuadrado A (2000) Inhibition of PKB/Akt1 by C2-ceramide involves activation of ceramide-activated protein phosphatase in PC12 cells. Mol Cell Neurosci 15:156–169

    Article  PubMed  CAS  Google Scholar 

  • Salinas M, Martin D, Alvarez A, Cuadrado A (2001) Akt1/PKBα protects PC12 cells against the parkinsonism-inducing neurotoxin 1-methyl-4-phenylpyridinium and reduces the levels of oxygen-free radicals. Mol Cell Neurosci 17:67–77

    Article  PubMed  CAS  Google Scholar 

  • Takagi S, Hayakawa N, Kimoto H, Kato H, Araki T (2007) Damage to oligodendrocytes in the striatum after MPTP neurotoxicity in mice. J Neural Transm 114:1553–1557

    Article  PubMed  CAS  Google Scholar 

  • Toescu EC, Verkhratsky A, Landfield PW (2004) Ca2+ regulation and gene expression in normal brain aging. Trends Neurosci 27:614–620

    Article  PubMed  CAS  Google Scholar 

  • Walton M, Woodgate AM, Muravlev A, Xu R, During MJ, Dragunow M (1999) CREB phosphorylation promotes nerve cell survival. J Neurochem 73:1836–1842

    PubMed  CAS  Google Scholar 

  • Wang HG, Pathan N, Ethell IM, Krajewski S, Yamaguchi Y, Shibasaki F, McKeon F, Bobo T, Franke TF, Reed JC (1999) Ca2+-induced apoptosis through calciunerin dephosphorylation of BAD. Science 284:339–343

    Article  PubMed  CAS  Google Scholar 

  • West MJ, Kawas CH, Stewart WF, Rudow GL, Troncoso JC (2004) Hippocampal neurons in pre-clinical Alzheimer’s disease. Neurobiol Aging 25:1205–1212

    Article  PubMed  CAS  Google Scholar 

  • Winder DG, Mansuy IM, Osman M, Moallem TM, Kandel ER (1998) Genetic and pharmacological evidence for a novel, intermediate phase of long-term potentiation suppressed by calcineurin. Cell 92:25–37

    Article  PubMed  CAS  Google Scholar 

  • Winder DG, Sweatt JD (2001) Roles of serine/threonine phosphatase in hippocampal synaptic plasticity. Nat Rev Neurosci 2:461–474

    Article  PubMed  CAS  Google Scholar 

  • Zhou H, Summers SA, Birnbaum MJ, Pittman RN (1998) Inhibition of Akt kinase by cell-permeable ceramide and its implications for ceramide-induced apoptosis. J Biol Chem 273:16568–16575

    Article  PubMed  CAS  Google Scholar 

  • Zhou M, Zhang W, Son H, Mansuy I, Sobel RA, Seidman J, Kandel ER (1999) A selective role of calcineurin Aα in synaptic depotentiation in hippocampus. Proc Natl Acad Sci USA 96:4650–4655

    Article  Google Scholar 

  • Zundel W, Giaccia A (1998) Inhibition of the anti-apoptotic PI(3)K/Akt/Bad pathway by stress. Genes Dev 12:1941–1946

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This study was supported in part by Grant-in-Aid for Scientific Research (136700627 and 13671095) from the Ministry of Science and Education in Japan.

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Authors and Affiliations

  1. Department of Neurobiology and Therapeutics, Graduate School and Faculty of Pharmaceutical Sciences, The University of Tokushima, 1-78, Sho-machi, Tokushima, 770-8505, Japan

    Risa Eto, Manami Abe, Natsumi Hayakawa & Tsutomu Araki

  2. Department of Neurology, Organized Center of Clinical Medicine, International University of Health and Welfare, Tochigi, Japan

    Hiroyuki Kato

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  1. Risa Eto
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  2. Manami Abe
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  3. Natsumi Hayakawa
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  4. Hiroyuki Kato
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  5. Tsutomu Araki
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Correspondence to Tsutomu Araki.

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Eto, R., Abe, M., Hayakawa, N. et al. Age-related changes of calcineurin and Akt1/protein kinase Bα (Akt1/PKBα) immunoreactivity in the mouse hippocampal CA1 sector: an immunohistochemical study. Metab Brain Dis 23, 399–409 (2008). https://doi.org/10.1007/s11011-008-9103-8

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