Skip to main content

Advertisement

SpringerLink
Log in

Disturbance of Intracellular Calcium Homeostasis and CaMKII/CREB Signaling is Associated with Learning and Memory Impairments Induced by Chronic Aluminum Exposure

  • Original Article
  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

Aluminum-induced neuronal injury has been implicated in various neurodegenerative disorders. However, the underlying mechanism involved in this pathogenesis still remains unknown. Our present findings demonstrated that chronic aluminum exposure resulted in spatial learning impairment and significantly increased intracellular calcium level in the hippocampus of rats. Examination of the associated protein molecules essential for induction and maintenance of long-term potentiation revealed that aluminum exposure could increase the expression level of calmodulin (CaM), but the expression levels of CaM-dependent protein kinase II (CaMKII), and phosphorylated cAMP-responsive element binding protein (CREB) were significantly reduced, whereas the total protein levels of CaMKII and CREB did not change in the aluminum-treated hippocampus. Thus, we provide a previously unrecognized mechanism whereby chronic aluminum exposure impairs hippocampal learning and memory, at least in part, through disruption of intracellular calcium homeostasis and CaM/CaMKII/CREB signaling pathway.

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

Similar content being viewed by others

References

  • Akasofu S, Kimura M, Kosasa T, Ogura H, Sawada K (2006) Protective effect of donepezil in primary-cultured rat cortical neurons exposed to N-methyl-d-aspartate (NMDA) toxicity. Eur J Pharmacol 530:215–222

    Article  CAS  PubMed  Google Scholar 

  • Alberini CM (2009) Transcription factors in long-term memory and synaptic plasticity. Physiol Rev 89(1):121–145

    Article  CAS  PubMed  Google Scholar 

  • Amici M, Doherty A, Jo J, Jane D, Cho K, Collingridge G, Dargan S (2009) Neuronal calcium sensors and synaptic plasticity. Biochem Soc Trans 37(Pt 6):1359–1363

    Article  CAS  PubMed  Google Scholar 

  • Barria A, Malinow R (2005) NMDA receptor subunit composition controls synaptic plasticity by regulating binding to CaMKII. Neuron 48(2):289–301

    Article  CAS  PubMed  Google Scholar 

  • Bishop GM, Robinson SR (2000) β-Amyloid helps to protect neurons against oxidative stress. Neurobiol Aging Suppl 21:S226

    Article  Google Scholar 

  • Brining SK, Jones CR, Chang MC (1996) Effects of chronic beta-amyloid treatment on fatty acid incorporation into rat brain. Neurobiol Aging 17:301–310

    Article  CAS  PubMed  Google Scholar 

  • Colomina MT, Roig JL, Sánchez DJ, Domingo JL (2002) Influence of age on Al-induced neurobehavioral effects and morphological changes in rat brain. Neurotoxicology 23(6):775–781

    Article  CAS  PubMed  Google Scholar 

  • Cui X, Wang B, Zong Z, Liu S, Xing W (2012) The effects of chronic Al exposure on learning and memory of rats by observing the changes of Ras/Raf/ERK signal transduction pathway. Food Chem Toxicol 50(2):315–319

    Article  CAS  PubMed  Google Scholar 

  • Exley C, Esiri MM (2006) Severe cerebral congophilic angiopathy coincident with increased brain aluminium in a resident of Camelford, Cornwall, UK. J Neurol Neurosurg Psychiatry 77(7):877–879

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fink CC, Meyer T (2002) Molecular mechanisms of CaMKII activation in neuronal plasticity. Curr Opin Neurobiol 12(3):293–299

    Article  CAS  PubMed  Google Scholar 

  • Flaten TP (2001) Aluminium as a risk factor in Alzheimer’s disease with emphasis on drinking water. Brain Res Bull 55(2):187–196

    Article  CAS  PubMed  Google Scholar 

  • Florence AL, Gauthier A, Ponsar C, Van den Bosch de Aguilar P, Crichton RR (1994) An experimental animal model of aluminium overload. Neurodegeneration 3(4):315–323

    CAS  PubMed  Google Scholar 

  • Games D, Adams D, Alesandrini R (1995) Alzheimer’s-type neuropathology in transgenic mice over expressing V71F beta amyloid precursor protein. Nature 373:523–527

    Article  CAS  PubMed  Google Scholar 

  • Gao HL, Xu H, Xin N, Zheng W, Chi ZH, Wang ZY (2011) Disruption of the CaMKII/CREB signaling is associated with zinc deficiency-induced learning and memory impairments. Neurotox Res 19(4):584–591

    Article  CAS  PubMed  Google Scholar 

  • Giese KP, Fedorov NB, Filipkowski RK, Silva AJ (1998) Autophosphorylation at Thr286 of the alpha calcium-calmodulin kinase II in LTP and learning. Science 279(5352):870–873

    Article  CAS  PubMed  Google Scholar 

  • Greger JL (1993) Aluminum metabolism. Annu Rev Nutr 13:43–63

    Article  CAS  PubMed  Google Scholar 

  • Guo GW, Liang YX (2001) Al-induced apoptosis in cultured astrocytes and its effect on calcium homeostasis. Brain Res 888(2):221–226

    Article  CAS  PubMed  Google Scholar 

  • Guzowski JF, Miyashita T, Chawla MK, Sanderson J, Maes LI, Houston FP, Lipa P, McNaughton BL, Worley PF, Barnes CA (2006) Recent behavioral history modifies coupling between cell activity and Arc gene transcription in hippocampal CA1 neurons. Proc Natl Acad Sci USA 103(4):1077–1082

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kaleka KS, Petersen AN, Florence MA, Gerges NZ (2012) Pull-down of calmodulin-binding proteins. J Vis Exp (59)

  • Kaur A, Gill KD (2005) Disruption of neuronal calcium homeostasis after chronic aluminium toxicity in rats. Basic Clin Pharmacol Toxicol 96(2):118–122

    Article  CAS  PubMed  Google Scholar 

  • Kawano T, Kadono T, Furuichi T, Muto S, Lapeyrie F (2003) Al-induced distortion in calcium signaling involving oxidative bursts and channel regulation in tobacco BY-2 cells. Biochem Biophys Res Commun 308(1):35–42

    Article  CAS  PubMed  Google Scholar 

  • Klatzo I, Wisniewski HM, Streicher E (1965) Experimental production of neurofibrillary degeneration. J Neuropath Exp Neurol 24:187–199

    Article  CAS  PubMed  Google Scholar 

  • Levi R, Wolf T, Fleminger G, Solomon B (1998) Immuno-detection of aluminium and aluminium induced conformational changes in calmodulin-implications in Alzheimer’s disease. Mol Cell Biochem 189(1–2):41–46

    Article  CAS  PubMed  Google Scholar 

  • Lisman J, Schulman H, Cline H (2002) The molecular basis of CaMKII function in synaptic and behavioural memory. Nat Rev Neurosci 3(3):175–190

    Article  CAS  PubMed  Google Scholar 

  • Lisman J, Yasuda R, Raghavachari S (2012) Mechanisms of CaMKII action in long-term potentiation. Nat Rev Neurosci 13(3):169–182

    CAS  PubMed  Google Scholar 

  • Malenka RC, Kauer JA, Perkel DJ, Mauk MD, Kelly PT, Nicoll RA, Waxham MN (1989) An essential role for postsynaptic calmodulin and protein kinase activity in long-term potentiation. Nature 340(6234):554–557

    Article  CAS  PubMed  Google Scholar 

  • Miyamoto E (2006) Molecular mechanism of neuronal plasticity: induction and maintenance of long-term potentiation in the hippocampus. J Pharmacol Sci 100(5):433–442

    Article  CAS  PubMed  Google Scholar 

  • Mizuno M, Yamada K, Maekawa N, Saito K, Seishima M, Nabeshima T (2002) CREB phosphorylation as a molecular marker of memory processing in the hippocampus for spatial learning. Behav Brain Res 133(2):135–141

    Article  CAS  PubMed  Google Scholar 

  • Pak JH, Huang FL, Li J, Balschun D, Reymann KG, Chiang C, Westphal H, Huang KP (2000) Involvement of neurogranin in the modulation of calcium/calmodulin-dependent protein kinase II, synaptic plasticity, and spatial learning: a study with knockout mice. Proc Natl Acad Sci USA 97:11232–11237

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Paxinos, Watson (2006) The rat brain in stereotaxic coordinates [M], 6th edn. Elseviev, London

    Google Scholar 

  • Perl DP, Good PF (1987) The association of aluminum Alzheimer’s disease, and neurofibrillary tangles. J Neural Transm Suppl 24:205–211

    CAS  PubMed  Google Scholar 

  • Perl DP, Moalem S (2006) Aluminum and Alzheimer’s disease, a personal perspective after 25 years. J Alzheimers Dis 9(3 Suppl):291–300

    CAS  PubMed  Google Scholar 

  • Petrik MS, Wong MC, Tabata RC, Garry RF, Shaw CA (2007) Al adjuvant linked to Gulf War illness induces motor neuron death in mice. Neuromolecular Med 9(1):83–100

    Article  CAS  PubMed  Google Scholar 

  • Porte Y, Buhot MC, Mons NE (2008) Spatial memory in the Morris water maze and activation of cyclic AMP response element-binding (CREB) protein within the mouse hippocampus. Learn Mem 15(12):885–894

    Article  PubMed  Google Scholar 

  • Raheja G, Gill KD (2002) Calcium homeostasis and dichlorvos induced neurotoxicity in rat brain. Mol Cell Biochem 232(1–2):13–18

    Article  CAS  PubMed  Google Scholar 

  • Sabine Spijker (2011) Neuroproteomics 57:13–26 doi:10.1007/978-1-61779-111-6_2

  • Sakaguchi M, Hayashi Y (2012) Catching the engram: strategies to examine the memory trace. Mol Brain 21(5):32

    Article  Google Scholar 

  • Saura CA, Valero J (2011) The role of CREB signaling in Alzheimer’s disease and other cognitive disorders. Rev Neurosci 22(2):153–169

    Article  CAS  PubMed  Google Scholar 

  • Solomon B, Koppel R, Jossiphov J (2001) Immunostaining of calmodulin and aluminium in Alzheimer’s disease-affected brains. Brain Res Bull 55(2):253–256

    Article  CAS  PubMed  Google Scholar 

  • Tomljenovic L (2011) Al and Alzheimer’s disease: after a century of controversy, is there a plausible link? J Alzheimers Dis 23(4):567–598

    CAS  PubMed  Google Scholar 

  • Tropea TF, Kosofsky BE, Rajadhyaksha AM (2008) Enhanced CREB and DARPP-32 phosphorylation in the nucleus accumbens and CREB, ERK, and GluR1 phosphorylation in the dorsal hippocampus is associated with cocaine-conditioned place preference behavior. J Neurochem 106(4):1780–1790

    Article  CAS  PubMed  Google Scholar 

  • Uno H, Aslum PB, Dong S (1999) Cerebral amyloid angiopathy and plaques, and visceral amyloidosis in aged macaques. Neurobiol Aging 17:275–282

    Article  Google Scholar 

  • Walton JR (2009) Functional impairment in aged rats chronically exposed to human range dietary aluminum equivalents. Neurotoxicology 30(2):182–193

    Article  CAS  PubMed  Google Scholar 

  • Walton JR (2012a) Aluminum disruption of calcium homeostasis and signal transduction resembles change that occurs in aging and Alzheimer’s disease. J Alzheimers Dis 29(2):255–273

    CAS  PubMed  Google Scholar 

  • Walton JR (2012b) Cognitive deterioration and associated pathology induced by chronic low-level aluminum ingestion in a translational rat model provides an explanation of Alzheimer’s disease, tests for susceptibility and avenues for treatment. Int J Alzheimers Dis 2012:914947

    CAS  PubMed Central  PubMed  Google Scholar 

  • Walton JR, Wang MX (2009) APP expression, distribution and accumulation are altered by aluminum in a rodent model for Alzheimer’s disease. J Inorg Biochem 103:1548–1554

    Article  CAS  PubMed  Google Scholar 

  • Wang B, Xing W, Zhao Y, Deng X (2010) Effects of chronic Al exposure on memory through multiple signal transduction pathways. Environ Toxicol Pharmacol 29(3):308–313

    Article  CAS  PubMed  Google Scholar 

  • Yumoto S, Kakimi S, Ohsaki A, Ishikawa A (2009) Demonstration of aluminum in amyloid fibers in the cores of senile plaques in the brains of patients with Alzheimer’s disease. J Inorg Biochem 103(11):1579–1584

    Article  CAS  PubMed  Google Scholar 

  • Zhong L, Cherry T, Bies CE, Florence MA, Gerges NZ (2009) Neurogranin enhances synaptic strength through its interaction with calmodulin. EMBO J 28:3027–3039

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by National Natural Science Foundation of China (81271292, 81000546 and 31000572), Scientific Research Foundation for Doctoral Program of Liaoning Province of China (20101148 and 20111110), New Teacher Fund for Doctor Station by Ministry of Education of China (20102104120013) and Funding of Scientific & Technological Projects for Abroad Students of Ministry of Human Resources and Social Security of China (2011LX001). China Postdoctoral Science Foundation (2012M520655).

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences of China Medical University Shenyang, No. 92 Bei’er Road, Heping District, Shenyang, 110001, People’s Republic of China

    Biao Wang, Xin Meng, Xin Cui, Yan Zhao, Wei Xing & Yifu Guan

  2. Department of Neurology, First Affiliated Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People’s Republic of China

    Jiuhan Zhao

  3. Key Laboratory of Transgenetic Animal Research, Department of Laboratory Animal of China Medical University, No. 92 Bei’er Road, Heping District, Shenyang, 110001, Liaoning Province, China

    Meng Yu

  4. Department of Urology, The First Affiliated Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, 110001, People’s Republic of China

    Yuyan Zhu

Authors
  1. Biao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jiuhan Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Meng Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xin Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xin Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yan Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuyan Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wei Xing
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yifu Guan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yifu Guan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, B., Zhao, J., Yu, M. et al. Disturbance of Intracellular Calcium Homeostasis and CaMKII/CREB Signaling is Associated with Learning and Memory Impairments Induced by Chronic Aluminum Exposure. Neurotox Res 26, 52–63 (2014). https://doi.org/10.1007/s12640-013-9451-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12640-013-9451-y

Keywords

Search

Navigation