Skip to main content

Advertisement

SpringerLink
Log in

Inhibition of Akt Phosphorylation Diminishes Mitochondrial Biogenesis Regulators, Tricarboxylic Acid Cycle Activity and Exacerbates Recognition Memory Deficit in Rat Model of Alzheimer’s Disease

  • Original Research
  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

3-Methyladenine (3-MA), as a PI3K inhibitor, is widely used for inhibition of autophagy. Inhibition of PI3K class I leads to inhibition of Akt phosphorylation, a central molecule involved in diverse arrays of intracellular cascades in nervous system. Accordingly, in the present study, we aimed to determine the alterations of specific mitochondrial biogenesis markers and mitochondrial function in 3-MA-injected rats following amyloid beta (Aβ) insult. Our data revealed that inhibition of Akt phosphorylation downregulates master regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Our data also showed that decrease in PGC-1α level presumably is due to decrease in the phosphorylation of cAMP-response element binding and AMP-activated kinase, two upstream activators of PGC-1α. As a consequence, the level of some mitochondrial biogenesis factors including nuclear respiratory factor-1, mitochondrial transcription factor A, and Cytochrome c decreased significantly. Also, activities of tricarboxylic acid cycle (TCA) enzymes such as Aconitase, a-ketoglutarate dehydrogenase, and malate dehydrogenase reduced in the presence of 3-MA with or without Aβ insult. Decrease in mitochondrial biogenesis factors and TCA enzyme activity in the rats receiving 3-MA and Aβ were more compared to the rats that received either alone; indicating the additive destructive effects of these two agents. In agreement with our molecular results, data obtained from behavioral test (using novel objective recognition test) indicated that inhibition of Akt phosphorylation with or without Aβ injection impaired novel recognition (non-spatial) memory. Our results suggest that 3-MA amplified deleterious effects of Aβ by targeting central molecule Akt.

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

Similar content being viewed by others

References

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

    Article  PubMed  CAS  Google Scholar 

  • Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  PubMed  CAS  Google Scholar 

  • Cantó C, Auwerx J (2009) PGC-1α, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr Opin Lipidol 20(2):98–105

    Article  PubMed  PubMed Central  Google Scholar 

  • Carling D, Mayer FV, Sanders MJ et al (2011) AMP-activated protein kinase: nature’s energy sensor. Nat Chem Biol 7(8):512–518

    Article  PubMed  CAS  Google Scholar 

  • Clarke JB, Nicklas WJ (1970) The metabolism of rat brain mitochondria; preparation and characterization. J Biol Chem 245(18):4724–4731

    Google Scholar 

  • Dagon Y, Avraham Y, Magen I et al (2005) Nutritional status, cognition, and survival: a new role for leptin and AMP kinase. J Biol Chem 280(51):42142–42148

    Article  PubMed  CAS  Google Scholar 

  • Du K, Montminy M (1998) CREB is a regulatory target for the protein kinase Akt/PKB. J Biol Chem 273(49):32377–32379

    Article  PubMed  CAS  Google Scholar 

  • Engelman JA, Luo J, Cantley LC (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7:606–619

  • Ennanceur A, Delacour J (1988) A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data. Behav Brain Res 31(1):47–59

    Article  Google Scholar 

  • Gibson GE, Starkov A, Blass JP et al (2010) Cause and consequence: mitochondrial dysfunction initiates and propagates neuronal dysfunction, neuronal death and behavioral abnormalities in age associated neurodegenerative diseases. Biochim Biophys Acta 1802(1):122–134

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Hayashi Y, Yoshida M, Yamato M et al (2008) Reverse of age-dependent memory impairment and mitochondrial DNA damage in microglia by an overexpression of human mitochondrial transcription factor A in mice. J Neurosci 28:8624–8634

    Article  PubMed  CAS  Google Scholar 

  • Herzig S, Long F, Jhala US et al (2001) CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature 413:179–183

    Article  PubMed  CAS  Google Scholar 

  • Johnson SC, Rabinovitch PS, Kaeberlein M (2013) mTOR is a key modulator of ageing and age-related disease. Nature 493(7432):338–345

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Kandel ER (2012) The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB. Mol Brain 5:1–14

    Article  Google Scholar 

  • Lin J, Handschin C, Spiegelman BM (2005) Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab 1:361–370

    Article  PubMed  Google Scholar 

  • Magnuson B, Ekim B, Fingar DC (2012) Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks. Biochem J 441:1–21

    Article  PubMed  CAS  Google Scholar 

  • Mayr B, Montminy M (2001) Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat Rev Mol Cell Biol 2(8):599–609

    Article  PubMed  CAS  Google Scholar 

  • Minoshima S, Giordani B, Berent S et al (1997) Metabolic reduction in the posterior cingulate cortex in very early Alzheimer’s disease. Ann Neurol 42:85–94

    Article  PubMed  CAS  Google Scholar 

  • Morishima-Kawashima M, Ihara Y (2002) Alzheimer’s disease: beta-amyloid protein and tau. J Neurosci Res 70(3):392–401

    Article  PubMed  CAS  Google Scholar 

  • Nulton-Persson AC, Szweda LI (2001) Modulation of mitochondrial function by hydrogen peroxide. J Biol Chem 276(26):23357–23361

    Article  PubMed  CAS  Google Scholar 

  • Onyango IG, Lu J, Rodova M et al (2010) Regulation of neuron mitochondrial biogenesis and relevance to brain health. Biochim Biophys Acta 1802:228–234

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates. Elsevier Academic press, San Diego

  • Powell CS, Jackson RM (2003) Mitochondrial complex I, aconitase, and succinate dehydrogenase during hypoxia-reoxygenation: modulation of enzyme activities by MnSOD. Am J Physiol 285(1):189–198

    Google Scholar 

  • Puigserver P, Spiegelman BM (2003) Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α): transcriptional coactivator and metabolic regulator. Endocr Rev 24(1):78–90

    Article  PubMed  CAS  Google Scholar 

  • Racker E (1950) Spectrophotometric measurements of the enzymatic formation of fumaric and cis-aconitic acids. Biochim Biophys Acta 4(1–3):211–214

    Article  PubMed  CAS  Google Scholar 

  • Sakamoto K, Karelina K, Obrietan K (2011) CREB: a multifaceted regulator of neuronal plasticity and protection. J Neurochem 116(1):1–9

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Scarpulla RC (2008) Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol Rev 88(2):611–638

    Article  PubMed  CAS  Google Scholar 

  • Scarpulla RC (2011) Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim Biophys Acta 1813(7):1269–1278

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Shaerzadeh F, Motamedi F, Minai-Tehrani D et al (2014) Monitoring of neuronal loss in the hippocampus of Aβ-injected rat: autophagy, mitophagy and mitochondrial biogenesis stand against apoptosis. Neuromolecular Med 16(1):175–190

    Article  PubMed  CAS  Google Scholar 

  • Steelman LS, Abrams SL, Whelan J et al (2008) Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia. Nat Rev Genet 7:606–619

    Google Scholar 

  • Thomas RR, Khan SM, Smigrodzki RM et al (2012) RhTFAM treatment stimulates mitochondrial oxidative metabolism and improves memory in aged mice. Aging 4(9):620–635

    PubMed  CAS  PubMed Central  Google Scholar 

  • Wang Q, Yu L, Yu CA (2010) Cross-talk between mitochondrial malate dehydrogenase and the cytochrome bc1 complex. J Biol Chem 285(14):10408–10414

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Wu Y, Tan H, Shui G et al (2010) Dual role of 3-methyladenine in modulation of autophagy via different temporal patterns of inhibition on class I and III phosphoinositide 3-kinase. J Biol Chem 285(14):10850–10861

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Zheng W, Ren S, Graziano JH (1998) Manganese inhibits mitochondrial aconitase: a mechanism of manganese neurotoxicity. Brain Res 799(2):334–342

    Article  PubMed  CAS  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work is part of PhD student thesis of F. Shaerzadeh at the Shahid Beheshti University of Medical Sciences. This work was supported by Neuroscience Research Center, Shahid Beheshti University of Medical Sciences Research Funds.

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

    Fatemeh Shaerzadeh, Fereshteh Motamedi & Fariba Khodagholi

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

    Fatemeh Shaerzadeh & Fereshteh Motamedi

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. 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

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shaerzadeh, F., Motamedi, F. & Khodagholi, F. Inhibition of Akt Phosphorylation Diminishes Mitochondrial Biogenesis Regulators, Tricarboxylic Acid Cycle Activity and Exacerbates Recognition Memory Deficit in Rat Model of Alzheimer’s Disease. Cell Mol Neurobiol 34, 1223–1233 (2014). https://doi.org/10.1007/s10571-014-0099-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-014-0099-9

Keywords

Search

Navigation