Skip to main content

Advertisement

SpringerLink
Log in

Monitoring of Neuronal Loss in the Hippocampus of Aβ-Injected Rat: Autophagy, Mitophagy, and Mitochondrial Biogenesis Stand Against Apoptosis

  • Original Paper
  • Published:
NeuroMolecular Medicine Aims and scope Submit manuscript

Abstract

In the present study, we tried to answer the following questions: which kind of defense pathways are activated after Aβ insult? How defense systems react against noxious effects of Aβ and whether they are able to deal against apoptosis or not? So, we traced some molecular pathways including autophagy, mitophagy, and mitochondrial biogenesis before reaching to the endpoint of apoptosis. Besides, we measured the function of mitochondria after injection of Aβ (1–42) in CA1 area of hippocampus as a model of Alzheimer’s disease (AD). Based on our data, autophagy markers reached to their maximum level and returned to the control level as apoptotic markers started to increase. As a specialized form of autophagy, mitophagy markers followed the trend of autophagy markers. Whereas mitochondrial dynamic processes shifted toward fission, mitochondrial biogenesis was severely affected by Aβ and significantly decreased. Alongside suppression of mitochondrial biogenesis, activity of specific enzymes involved in antioxidant defense system, electron transport chain, and tricarboxylic acid cycle (TCA) decreased in response to the Aβ. Activity of antioxidant enzymes increased at first and then decreased significantly compared to the control. TCA enzymes aconitase and malate dehydrogenase activities reduced immediately while citrate synthase and fumarase activities did not change. Based on our finding, monitoring of the master molecules of intracellular cascades and determining their trends before the destructive function of Aβ could be the target of therapeutic issues for AD.

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
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Scheme 1

Similar content being viewed by others

References

  • Adam-Vizi, V., & Chinopoulos, C. (2006). Bioenergetics and the formation of mitochondrial reactive oxygen species. Trends in Pharmacological Sciences, 27(12), 639–645.

    Article  CAS  PubMed  Google Scholar 

  • Aebi, H. (1984). Catalase in vitro. Methods in Enzymology, 105, 121–126.

    Article  CAS  PubMed  Google Scholar 

  • Ashrafi, G., & Schwarz, T. L. (2013). The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differentiation, 20(1), 31–42.

    Article  CAS  PubMed  Google Scholar 

  • Birch-Machin, M. A., Shepherd, I. M., Watmough, N. J., Sherrat, H. S., Bartlett, K., Darley-Usmar, V. M., et al. (1989). Fatal lactic acidosis in infancy with a defect of complex III of the respiratory chain. Pediatric Research, 25, 553–559.

    Article  CAS  PubMed  Google Scholar 

  • Boengler, K., Heusch, G., & Schulz, R. (2011). Nuclear-encoded mitochondrial proteins and their role in cardioprotection. Biochimica et Biophysica Acta, 1813(7), 1286–1294.

    Article  CAS  PubMed  Google Scholar 

  • Braak, H., & Braak, E. (1991). Demonstration of amyloid deposits and neurofibrillary changes in whole brain sections. Brain Pathology, 1(3), 213–216.

    Article  CAS  PubMed  Google Scholar 

  • Bradford, M. M. (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Analytical Biochemistry, 72, 248–254.

    Article  CAS  PubMed  Google Scholar 

  • Bubber, P., Haroutunian, V., Fisch, G., Parvesh, B., & Vahram, H. (2005). Mitochondrial abnormalities in Alzheimer brain: Mechanistic implications. Annals of Neurology, 57, 695–703.

    Article  CAS  PubMed  Google Scholar 

  • Chen, H., Chan, D. C. (2009). Mitochondrial dynamics—Fusion, fission, movement, and mitophagy—In neurodegenerative diseases. Human Molecular Genetics, 18 (R2), R169–R176.

    Google Scholar 

  • Christen, Y. (2000). Oxidative stress and Alzheimer disease. The American Journal of Clinical Nutrition, 71(2), 621S–629S.

    CAS  PubMed  Google Scholar 

  • Cipolat, S., Martins de Brito, O., Dal Zilio, B., & Scorrano, L. (2004). OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proceedings of the National Academy of Sciences, 101(45), 15927–15932.

    Article  CAS  Google Scholar 

  • Clarke, J. B., & Nicklas, W. J. (1970). The metabolism of rat brain mitochondria preparation and characterization. Journal of Biological Chemistry, 245(18), 4724–4731.

    Google Scholar 

  • Cottingham, M. G., Hollinshead, M. S., & Vaux, D. J. (2002). Amyloid fibril formation by a synthetic peptide from a region of human acetylcholinesterase that is homologous to the Alzheimer’s amyloid-beta peptide. Biochemistry, 41(46), 13539–13547.

    Article  CAS  PubMed  Google Scholar 

  • Cunningham, J. T., Rodgers, J. T., Arlow, D. H., Vazquez, F., Mootha, V. K., & Puigserver, P. (2007). mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature, 450(7170), 736–740.

    Article  CAS  PubMed  Google Scholar 

  • Darios, F., Corti, O., Lucking, C. B., Hampe, C., Muriel, M. P., Abbas, N., et al. (2003). Parkin prevents mitochondrial swelling and cytochrome c release in mitochondria-dependent cell death. Human Molecular Genetics, 12, 517–526.

    Article  CAS  PubMed  Google Scholar 

  • De Duve, C., & Wattiaux, R. (1966). Functions of lysosomes. Annual Review of Physiology, 28, 435–492.

    Article  PubMed  Google Scholar 

  • Eisenberg-Lerner, A., Bialik, S., Simon, H.-U., & Kimchi, A. (2009). Life and death partners: Apoptosis, autophagy and the cross-talk between them. Cell Death and Differentiation, 16, 966–975.

    Article  CAS  PubMed  Google Scholar 

  • Ellman, G. L. (1959). Tissue sulfhydryl groups. Archives of Biochemistry and Biophysics, 82, 70–77.

    Article  CAS  PubMed  Google Scholar 

  • Flint, D. H., Tuminello, J. F., & Emptage, M. H. (1993). The inactivation of Fe–S cluster containing hydro-lyases by superoxide. Journal of Biological Chemistry, 268, 22369–22376.

    CAS  PubMed  Google Scholar 

  • Fujita, N., Noda, T., & Yoshimori, T. (2009). Atg4BC74A hampers autophagosome closure: A useful protein for inhibiting autophagy. Autophagy, 5(1), 88–89.

    Article  CAS  PubMed  Google Scholar 

  • Gardner, P. R., Raineri, I., Epstein, L. B., & White, C. W. (1995). Superoxide radical and iron modulate aconitase activity in mammalian cells. Journal of Biological Chemistry, 270, 13399–13405.

    Article  CAS  PubMed  Google Scholar 

  • Glenner, G. G., & Wong, C. W. (1984). Alzheimer’s disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochemical and Biophysical Research Communications, 120, 885–890.

    Article  CAS  PubMed  Google Scholar 

  • Gleyzer, N., Vercauteren, K., & Scarpulla, R. C. (2005). Control of mitochondrial transcription specificity factors (TFB1 M and TFB2 M) by nuclear respiratory factors (NRF-1 and NRF-2) and PGC-1 family coactivators. Molecular Cell Biology, 25(4), 1354–1366.

    Article  CAS  Google Scholar 

  • Goldberg, A. L. (2003). Protein degradation and protection against misfolded or damaged proteins. Nature, 426, 895–899.

    Article  CAS  PubMed  Google Scholar 

  • Haass, C., & Selkoe, D. J. (2007). Soluble protein oligomers in neurodegeneration: Lessons from the Alzheimer’s amyloid b-peptide. Nature Reviews Molecular Cell Biology, 8, 101–112.

    Article  CAS  PubMed  Google Scholar 

  • Hara, T., Nakamura, K., Matsui, M., Yamamoto, A., Nakahara, Y., Suzuki-Migishima, R., et al. (2006). Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature, 441, 885–889.

    Article  CAS  PubMed  Google Scholar 

  • Heinonen, H., Nieminen, A., Saarela, M., Kallioniemi, A., Klefström, J., Hautaniemi, S., et al. (2008). Deciphering downstream gene targets of PI3 K/mTOR/p70S6 K pathway in breast cancer. BMC Genomics, 2008(9), 348–360.

    Article  Google Scholar 

  • Hui Bon Hoa, G., McLean, M. A., & Sligar, S. G. (2002). High pressure, a tool for exploring heme protein active sites. Biochimica et Biophysica Acta, 1595(1–2), 297–308.

    Article  CAS  PubMed  Google Scholar 

  • Jones, D. P. (2002). Redox potential of GSH/GSSG couple: Assay and biological significance. Methods in Enzymology, 348, 93–112.

    Article  CAS  PubMed  Google Scholar 

  • Jones, C. W., & Poole, R. K. (1985). The analysis of cytochromes. Methods of microbiology, 18, 285–328.

    Article  CAS  Google Scholar 

  • Kakkar, P., Das, B., & Viswanathan, P. N. (1984). A modified spectrophotometric assay of superoxide dismutase. Indian Journal of Biochemistry & Biophysics, 21, 130–132.

    CAS  Google Scholar 

  • Kim, H. C., Yamada, K., Nitta, A., Olariu, A., Tran, M. H., Mizuno, M., et al. (2003). Immunocytochemical evidence that amyloid beta (1–42) impairs endogenous antioxidant systems in vivo. Neuroscience, 119, 399–419.

    Article  CAS  PubMed  Google Scholar 

  • Klionsky, D. J., Cregg, J. M., Dunn, W. A., Jr, Emr, S. D., Sakai, Y., Sandoval, I. V., et al. (2003). A unified nomenclature for yeast autophagy-related genes. Developmental Cell, 5, 539–545.

    Article  CAS  PubMed  Google Scholar 

  • Kohler, J. J., Cucoranu, I., Fields, E., Green, E., He, S., Hoying, A., et al. (2009). Transgenic mitochondrial superoxide dismutase and mitochondrially targeted catalase prevent antiretroviral-induced oxidative stress and cardiomyopathy. Laboratory Investigation, 89(7), 782–790.

    Article  CAS  PubMed  Google Scholar 

  • Komatsu, M., Waguri, S., Chiba, T., Murata, S., Iwata, J., Tanida, I., et al. (2006). Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature, 441, 880–884.

    Article  CAS  PubMed  Google Scholar 

  • Lamark, T., Kirkin, V., Dikic, I., & Johansen, T. (2009). NBR1 and p62 as cargo receptors for selective autophagy of ubiquitinated targets. Cell Cycle, 8(13), 1986–1990.

    Article  CAS  PubMed  Google Scholar 

  • Levine, B., & Kroemer, G. (2008). Autophagy in the pathogenesis of disease. Cell, 132, 27–42.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Li, W., Yang, Q., & Mao, Z. (2011). Chaperone-mediated autophagy: machinery, regulation and biological consequences. Cellular and Molecular Life Sciences, 68, 749–763.

    Article  CAS  PubMed  Google Scholar 

  • Manczak, M., Park, B. S., Jung, Y., & Reddy, P. H. (2004). Differential expression of oxidative phosphorylation genes in patients with Alzheimer’s disease: Implications for early mitochondrial dysfunction and oxidative damage. NeuroMolecular Medicine, 5, 147–162.

    Article  CAS  PubMed  Google Scholar 

  • Minoshima, S., Giordani, B., Berent, S., Frey, K. A., Foster, N. L., & Kuhl, D. E. (1997). Metabolic reduction in the posterior cingulate cortex in very early Alzheimer’s disease. Annals of Neurology, 42, 85–94.

    Article  CAS  PubMed  Google Scholar 

  • Morán, M., Moreno-Lastres, D., Marín-Buera, L., Arenas, J., Martín, M. A., & Ugalde, C. (2012). Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration. Free Radical Biology & Medicine, 53, 595–609.

    Article  Google Scholar 

  • Morishima, Y., Gotoh, Y., Zieg, J., Barrett, T., Takano, H., Flavell, R., et al. (2001). β-Amyloid induces neuronal apoptosis via a mechanism that involves the c-Jun N-Terminal kinase pathway and the induction of Fas ligand. Journal of Neuroscience, 21(19), 7551–7560.

    CAS  PubMed  Google Scholar 

  • Morishima-Kawashima, M., & Ihara, Y. (2002). Alzheimer’s disease: Beta-Amyloid protein and tau. Journal of Neuroscience Research, 70(3), 392–401.

    Article  CAS  PubMed  Google Scholar 

  • Muller, F. L., Liu, Y., & Van Remmen, H. (2004). Complex III releases superoxide to both sides of the inner mitochondrial membrane. Journal of Biological Chemistry, 279, 49064–49073.

    Article  CAS  PubMed  Google Scholar 

  • Murphy, M. P. (2009). How mitochondria produce reactive oxygen species. Biochemical Journal, 417(Pt 1), 1–13.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Narendra, D. P., & Youle, R. J. (2011). Targeting mitochondrial dysfunction: Role for PINK1 and Parkin in mitochondrial quality control. Antioxidants & Redox Signaling, 14(10), 1929–1938.

    Article  CAS  Google Scholar 

  • Patel, M., Day, B. J., Crapo, J. D., Fridovich, I., & McNamara, J. O. (1996). Requirement for superoxide in excitotoxic cell death. Neuron, 16, 345–355.

    Article  CAS  PubMed  Google Scholar 

  • Paxinos, G., & Watson, C. (2007). The rat brain in stereotaxic coordinates. Amsterdam: Elsevier Academic press.

    Google Scholar 

  • Powell, C. S., & Jackson, R. M. (2003). Mitochondrial complex I, aconitase, and succinate dehydrogenase during hypoxia-reoxygenation: Modulation of enzyme activities by MnSOD. American Journal of Physiology, 285(1), L189–L198.

    CAS  PubMed  Google Scholar 

  • Qi, Z., & Ding, S. (2012). Transcriptional regulation by nuclear corepressors and PGC-1α: Implications for mitochondrial quality control and insulin sensitivity. PPAR Research, 2012, 1–12.

    Article  Google Scholar 

  • Racker, E. (1950). Spectrophotometric measurements of the enzymatic formation of fumaric and cis-aconitic acids. Biochimica et Biophysica Acta, 4(1–3), 211–214.

    Article  CAS  PubMed  Google Scholar 

  • Ravikumar, B., Futter, M., Jahreiss, L., Korolchuk, V. I., Lichtenberg, M., Luo, S., et al. (2009). Mammalian macroautophagy at a glance. Journal of Cell Science, 122, 1707–1711.

    Article  CAS  PubMed  Google Scholar 

  • Rhein, V., Baysang, G., Rao, S., Meier, F., Bonert, A., Muller-Spahn, F., et al. (2009). Amyloid-beta leads to impaired cellular respiration, energy production and mitochondrial electron chain complex activities in human neuroblastoma Cells. Cellular and Molecular Neurobiology, 29, 1063–1071.

    Article  CAS  PubMed  Google Scholar 

  • Rubinsztein, D. C. (2006). The roles of intracellular protein-degradation pathways in neurodegeneration. Nature, 443, 780–786.

    Article  CAS  PubMed  Google Scholar 

  • Rustin, P., Chretien, D., Bourgeron, T., Wucher, A., Saudubray, J. M., Rotig, A., et al. (1991). Assessment of the mitochondrial respiratory chain. Lancet, 338, 60.

    Article  CAS  PubMed  Google Scholar 

  • Sahu, R., Kaushik, S., Clement, C. C., Cannizzo, E. S., Scharf, B., Follenzi, A., et al. (2011). Microautophagy of cytosolic proteins by late endosomes. Developmental Cell, 20(3), 405–406.

    Article  CAS  Google Scholar 

  • Saikumar, P., Dong, Z., Mikhailov, V., Denton, M., Weimberg, J. M., & Venkatachalam, M. A. (1999). Apoptosis: Definition, mechanisms, and relevance to disease. American Journal of Medicine, 107(5), 489–506.

    Article  CAS  PubMed  Google Scholar 

  • Santos, R. X., Correia, S. C., Wang, X., Perry, G., Smith, M. A., Moreira, P. I., et al. (2010). A synergistic dysfunction of mitochondrial fission/fusion dynamics and mitophagy in Alzheimer’s disease. Journal of Alzheimers Disease, 2, S401–S412.

    Google Scholar 

  • Sazanov, L. A. (2007). Respiratory complex I: Mechanistic and structural insights provided by the crystal structure of the hydrophilic domain. Biochemistry, 46, 2275–2288.

    Article  CAS  PubMed  Google Scholar 

  • Scarpulla, R. C. (2002). Nuclear activators and coactivators in mammalian mitochondrial biogenesis. Biochimica et Biophysica Acta, 1576(1–2), 1–14.

    Article  CAS  PubMed  Google Scholar 

  • Scarpulla, R. C. (2011). Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochimica et Biophysica Acta, 1813(7), 1269–1278.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Schweichel, J. U., & Merker, H. J. (1973). The morphology of various types of cell death in prenatal tissues. Teratology, 7, 253–266.

    Article  CAS  PubMed  Google Scholar 

  • Small, D. H., Gasperini, R., Vincent, A. J., Hung, A. C., & Foa, L. (2009). The role of Abeta-induced calcium dysregulation in the pathogenesis of Alzheimer’s disease. Journal of Alzheimers Disease, 16, 225–233.

    CAS  Google Scholar 

  • Srere, P. A. (1974). Controls of citrate synthase. Life. Science, 15, 1695–1710.

    CAS  Google Scholar 

  • Stadelmann, C., Deckwerth, T. L., Srinivasan, A., Bancher, C., Brück, W., Jellinger, K., et al. (1999). Activation of caspase-3 in single neurons and autophagic granules of granulovacuolar degeneration in Alzheimer’s disease. Evidence for apoptotic cell death. American Journal of Pathology, 155(5), 1459–1466.

    Article  CAS  PubMed  Google Scholar 

  • Tanida, I. (2011). Autophagy basics. Microbiology and Immunology, 55, 1–11.

    Article  CAS  PubMed  Google Scholar 

  • Troy, C. M., Rabacchi, S. A., Friedman, W. J., Frappier, T. F., Brown, K., & Shelanski, M. L. (2000). Caspase-2 mediates neuronal cell death induced by β-amyloid. Journal of Neuroscience, 20(4), 1386–1392.

    CAS  PubMed  Google Scholar 

  • Tuppoa, E. E., & Arias, H. R. (2009). The role of inflammation in Alzheimer’s disease. International Journal of Biochemistry & Cell Biology, 37, 289–305.

    Article  Google Scholar 

  • Veereshwarayya, V., Kumar, P., Rosen, K. M., Mestril, R., & Querfurth, H. W. (2006). Differential effects of mitochondrial heat shock protein 60 and related molecular chaperones to prevent intracellular β-amyloid-induced inhibition of complex IV and limit apoptosis. Journal of Biological Chemistry, 281, 29468–29478.

    Article  CAS  PubMed  Google Scholar 

  • Vitolo, O. V., Sant’Angelo, A., Costanzo, V., Battaglia, F., Arancio, O., & Shelanski, M. (2002). Amyloid beta-peptide inhibition of the PKA/CREB pathway and long-term potentiation: Reversibility by drugs that enhance cAMP signaling. Proceedings of the National Academy of Sciences, 99(20), 13217–13221.

    Article  CAS  Google Scholar 

  • Wang, L., Mascher, H., Psilander, N., Blomstrand, E., & Sahlin, K. (2011). Resistance exercise enhances the molecular signaling of mitochondrial biogenesis induced by endurance exercise in human skeletal muscle. Journal of Applied Physiology, 111, 1335–1344.

    Article  CAS  PubMed  Google Scholar 

  • Wang, Q., Yu, L., & Yu, C. A. (2010). Cross-talk between mitochondrial malate dehydrogenase and the cytochrome bc1 complex. Journal of Biological Chemistry, 285(14), 10408–10414.

    Article  CAS  PubMed  Google Scholar 

  • Watson, D., Castano, E., Kokjohn, T. A., Kuo, Y. M., Lyubchenko, Y., et al. (2005). Physicochemical characteristics of soluble oligomeric Aβ and their pathologic role in Alzheimer’s disease. Journal of Neurology Research, 27, 869–881.

    Article  CAS  Google Scholar 

  • Wenz, T. (2013). Regulation of mitochondrial biogenesis and PGC-1α under cellular stress. Mitochondrion, 13(2), 134–142.

    Article  CAS  PubMed  Google Scholar 

  • Yan, S. D., Chen, X., Fu, J., Chen, M., & Zhu, H. (1996). RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature, 382, 685–691.

    Article  CAS  PubMed  Google Scholar 

  • Yu, W. H., Cuervo, A. M., Kumar, A., Peterhoff, C. M., Schmidt, S. D., Lee, J. H., et al. (2005). Macroautophagy—A novel beta-amyloid peptide-generating pathway activated in Alzheimer’s disease. Journal of Cell Biology, 171(1), 87–98.

    Article  CAS  PubMed  Google Scholar 

  • Yu, L., & Yang, S. J. (2010). AMP-activated protein kinase mediates activity-dependent regulation of peroxisome proliferator-activated receptor gamma coactivator-1alpha and nuclear respiratory factor 1 expression in rat visual cortical neurons. Neuroscience, 169(1), 23–38.

    Article  CAS  PubMed  Google Scholar 

  • Zheng, W., Ren, S., & Graziano, J. H. (1998). Manganese inhibits mitochondrial aconitase: A mechanism of manganese neurotoxicity. Brain Reseach, 799(2), 334–342.

    Article  CAS  Google Scholar 

  • Zhu, J., Wang, K. Z. Q., & Chu, C. T. (2013). After the banquet: Mitochondrial biogenesis, mitophagy and cell survival. Autophagy, 9(9), 1–14.

    Google Scholar 

Download references

Acknowledgments

This work is part of PhD student thesis of F. Shaerzadeh at the Shahid Beheshti University of Medical Sciences.

Conflict of interest

The authors have no conflict of interest.

Author information

Authors and Affiliations

  1. NeuroBiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Fatemeh Shaerzadeh, Fereshteh Motamedi & Fariba Khodagholi

  2. Neurophysiology Research Center, Department of Physiology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Fatemeh Shaerzadeh & Fereshteh Motamedi

  3. Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Fatemeh Shaerzadeh, Fereshteh Motamedi & Fariba Khodagholi

  4. Bioresearch Lab, Faculty of Biological Sciences, Shahid Beheshti University G.C., Tehran, Iran

    Dariush Minai-Tehrani

Authors
  1. Fatemeh Shaerzadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fereshteh Motamedi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dariush Minai-Tehrani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fariba Khodagholi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fariba Khodagholi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shaerzadeh, F., Motamedi, F., Minai-Tehrani, D. et al. Monitoring of Neuronal Loss in the Hippocampus of Aβ-Injected Rat: Autophagy, Mitophagy, and Mitochondrial Biogenesis Stand Against Apoptosis. Neuromol Med 16, 175–190 (2014). https://doi.org/10.1007/s12017-013-8272-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12017-013-8272-8

Keywords

Search

Navigation