Abstract
Aluminum (Al) is an environmental neurotoxin with extensive exposure by humans, but the molecular mechanism of its toxicity is still unclear. Several studies have indicated that exposure to aluminum can impair learning and memory function. The purpose of this study was to investigate the mechanism of LTP injury and the effect of aluminum exposure on related signal pathways. The results showed that the axonal dendrites of neurons in the hippocampal CA1 area of rats exposed to maltol aluminum showed neuritic beading and the dendritic spines were reduced. This resulted in dose-dependent LTP inhibition and led to impaired learning and memory function in rats. The PI3K-Akt-mTOR pathway may play a crucial role in this process.
Similar content being viewed by others
Abbreviations
- LTP:
-
Long-term potentiation
- PI3K:
-
Phosphatidylinositol 3-kinase
- Akt:
-
Protein kinase B
- mTOR:
-
Mammalian target of rapamycin
- AMPAR:
-
α-Amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor
References
Adamiec R, Uzar J (1988) The role of aluminum in the development of osteomalacia in patients on chronic hemodialysis. Pol Arch Med Wewn 79(1):3
Bakar C, Karaman HI, Baba A, Sengünalp F (2009) Effect of high aluminum concentration in water resources on human health, case study: Biga peninsula, northwest part of Turkey. Arch Environ Contam Toxicol 58(4):935–944
Bakar C, Kun B et al (2010) Effect of high aluminum concentration in water resources on human health, case study: Biga Peninsula, northwest part of Turkey. Arch Environ Contam Toxicol 58(4):935–944
Bliss TV, Lomo T (1973) Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol 232(2):331–356
Bondy SBC (2010) The neurotoxicity of environmental aluminum is still an issue. Neurotoxicology 31(5):575–581
Borrie SC et al (2017) Cognitive dysfunctions in intellectual disabilities: the contributions of the Ras-MAPK and PI3K-AKT-mTOR pathways. Annu Rev Genomics Hum Genet 18:115
Clements MP, Bliss TV, Lynch MA (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361(6407):31–39
Dabeka R et al (2011) Lead, cadmium and aluminum in Canadian infant formulae, oral electrolytes and glucose solutions. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 28(6):744–753
Delisle MB, Carpenter S (1984) Neurofibrillary axonal swellings and amyotrophic lateral sclerosis. J Neurol Sci 63(2):241–250
Dickson TC, King CE, McCormack G, Vickers JC (1999) Neurochemical diversity of dystrophic neurites in the early and late stages of Alzheimer's disease. Exp Neurol 156(1):100–110
Divine KK, Lewis JL, Grant PG, Bench G (1999) Quantitative particle-induced X-ray emission imaging of rat olfactory epithelium applied to the permeability of rat epithelium to inhaled aluminum. Chem Res Toxicol 12(7):575–581
Flaten TP (2001) Aluminium as a risk factor in Alzheimer’s disease, with emphasis on drinking water. Brain Res Bull 55(2):187–196
Goel S et al (2010) Morphological changes and stress responses in neurons in cerebral cortex infiltrated by diffuse astrocytoma. Neuropathology 23(4):262–270
Gruart A, Muñoz MD, Delgado-García JM (2006) Involvement of the CA3-CA1 synapse in the acquisition of associative learning in behaving mice. J Neurosci Off J Soc Neurosci 26(4):1077–1087
Hayashi Y, Shi SH, Esteban JA, Piccini A, Poncer JC, Malinow R (2000) Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction. Science 287(5461):2262–2267
He SC, Qiao N, Sheng W (2003) Neurobehavioral, autonomic nervous function and lymphocyte subsets among aluminum electrolytic workers. Int J Immunopathol Pharmacol 16(2):139–144
Hideyuki T et al (2005) Neuritic beading induced by activated microglia is an early feature of neuronal dysfunction toward neuronal death by inhibition of mitochondrial respiration and axonal transport. J Biol Chem 280(11):10444–10454
Hori N, Carpenter DO (1994) Functional and morphological changes induced by transient in vivo ischemia. Exp Neurol 129(2):279–289
Huganir RL, Nicoll RA (2013) AMPARs and synaptic plasticity: the last 25 years. Neuron 80(3):704–717
Ikegaya Y, Kim JA, Baba M, Iwatsubo T, Nishiyama N, Matsuki N (2001) Rapid and reversible changes in dendrite morphology and synaptic efficacy following NMDA receptor activation: implication for a cellular defense against excitotoxicity. J Cell Sci 114(Pt 22):4083–4093
Jing S et al (2016) The RAS/PI3K pathway is involved in the impairment of long-term potentiation induced by acute aluminum treatment in rats. Biomed Environ Sci 29(11):782–789
Kandimalla R, Vallamkondu J, Corgiat EB, Gill KD (2016) Understanding aspects of aluminum exposure in Alzheimer’s disease development. Brain Pathol 26(2):139–154
Khalifa M et al., Telmisartan protects against aluminum-induced alzheimer-like pathological changes in rats. Neurotoxicity research, 2019. undefined (undefined): p. undefined
Krewski D et al (2007) Human health risk assessment for aluminium, aluminium oxide, and aluminium hydroxide. J Toxicol Environ Health Part B 10(sup1):1–269
Liang RF, Li WQ, Wang XH, Zhang HF, Wang H, Wang JX, Zhang Y, Wan MT, Pan BL, Niu Q (2012) Aluminium-maltolate-induced impairment of learning, memory and hippocampal long-term potentiation in rats. Ind Health 50(5):428–436
Lisman JE, Goldring MA (1988) Feasibility of long-term storage of graded information by the Ca2+/calmodulin-dependent protein kinase molecules of the postsynaptic density. Proc Natl Acad Sci U S A 85(14):5320–5324
Liu Q et al (2014) Akt and mTOR mediate programmed necrosis in neurons. Cell Death Dis 5(2):e1084
Lu X, Liang R, Jia Z, Wang H, Pan B, Zhang Q, Niu Q (2014) Cognitive disorders and tau-protein expression among retired aluminum smelting workers. J Occup Environ Med 56(2):155–160
Lynch G, Cox CD, Gall CM (2014) Pharmacological enhancement of memory or cognition in normal subjects. Front Syst Neurosci 8(8):90
Martini M, de Santis MC, Braccini L, Gulluni F, Hirsch E (2014) PI3K/AKT signaling pathway and cancer: an updated review. Ann Med 46(6):372–383
Mathis DM, Furman JL, and Norris CM, Preparation of acute hippocampal slices from rats and transgenic mice for the study of synaptic alterations during aging and amyloid pathology. J Vis Exp, 2011(49)
Mattila PM, Rinne JO, Helenius H, Röyttä M (1999) Neuritic degeneration in the hippocampus and amygdala in Parkinson’s disease in relation to Alzheimer pathology. Acta Neuropathol 98(2):157–164
Meyerbaron M et al (2007) Occupational aluminum exposure: evidence in support of its neurobehavioral impact. Neurotoxicology 28(6):1068–1078
Mitrofanis P et al (2003) Retinal ganglion cells resistant to advanced glaucoma: a postmortem study of human retinas with the carbocyanine dye DiI. Invest Ophthalmol Vis Sci 44(12):5196–5205
Morris R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 11(1):47–60
Nicoll RA (2017) A brief history of long-term potentiation. Neuron 93(2):281–290
Norman KA (2010) How hippocampus and cortex contribute to recognition memory: revisiting the complementary learning systems model. Hippocampus 20(11):1217–1227
Park JS, Bateman MC, Goldberg MP (1996) Rapid alterations in dendrite morphology during sublethal hypoxia or glutamate receptor activation. Neurobiol Dis 3(3):215–227
Paxinos G, Watson C, Pennisi M, Topple A (1985) Bregma, lambda and the interaural midpoint in stereotaxic surgery with rats of different sex, strain and weight. J Neurosci Methods 13(2):139–143
Petrik MS, Wong MC, Tabata RC, Garry RF, Shaw CA (2007) Aluminum adjuvant linked to Gulf War illness induces motor neuron death in mice. NeuroMolecular Med 9(1):83–100
Plant K, Pelkey KA, Bortolotto ZA, Morita D, Terashima A, McBain C, Collingridge GL, Isaac JT (2006) Transient incorporation of native GluR2-lacking AMPA receptors during hippocampal long-term potentiation. Nat Neurosci 9(5):602–604
Polizzi S, Pira E, Ferrara M, Bugiani M, Papaleo A, Albera R, Palmi S (2002) Neurotoxic effects of aluminium among foundry workers and Alzheimer's disease. Neurotoxicology 23(6):761–774
Ren P, Kang P, Li Z, Zhang H, Niu Q (2017) Impact of chronic aluminum exposure on NMDAR1 in the cortex and peripheral blood lymphocytes in rats. Wei Sheng Yan Jiu 46(1):15–20
Roediger B, Armati PJ (2003) Oxidative stress induces axonal beading in cultured human brain tissue. Neurobiol Dis 13(3):222–229
Saito Y, Kawashima A, Ruberu NN, Fujiwara H, Koyama S, Sawabe M, Arai T, Nagura H, Yamanouchi H, Hasegawa M, Iwatsubo T, Murayama S (2003) Accumulation of phosphorylated alpha-synuclein in aging human brain. J Neuropathol Exp Neurol 62(6):644–654
Sandra J (2018) AMPA receptor trafficking in natural and pathological aging. Front Mol Neurosci 10:446
Shu Y, Zhang H, Kang T, Zhang JJ, Yang Y, Liu H, Zhang L (2013) PI3K/Akt signal pathway involved in the cognitive impairment caused by chronic cerebral hypoperfusion in rats. PLoS One 8(12):e81901
Silva AJ, Stevens CF, Tonegawa S, Wang Y (1992) Deficient hippocampal long-term potentiation in alpha-calcium-calmodulin kinase II mutant mice. Science 257(5067):201–206
Song J, Liu Y, Zhang HF, Zhang QL, Niu Q (2014) Effects of exposure to aluminum on long-term potentiation and AMPA receptor subunits in rats in vivo. Biomed Environ Sci 27(2):77–84
Swann JW et al (2015) Spine loss and other dendritic abnormalities in epilepsy. Hippocampus 10(5):617–625
Takahashi T, Yagishita S, Amano N, Yamaoka K, Kamei T (1997) Amyotrophic lateral sclerosis with numerous axonal spheroids in the corticospinal tract and massive degeneration of the cortex. Acta Neuropathol 94(3):294–299
Tomljenovic L, Shaw CA (2011) Aluminum vaccine adjuvants: are they safe? Curr Med Chem 18(17):2630–2637
Verma S, Ranawat P, Sharma N, Nehru B et al (2019) Ginkgo biloba attenuates aluminum lactate-induced neurotoxicity in reproductive senescent female rats: behavioral, biochemical, and histopathological study. Environ Sci Pollut Res Int 26(26):27148–27167
Williams RJ (1997) The natural selection of the chemical elements. Cell Mol Life Sci Cmls 53(10):816–829
Xu Y et al (2018) Transcriptome-wide identification of differentially expressed genes and long non-coding RNAs in aluminum-treated rat hippocampus. Neurotox Res 4(2):220–232 1–13
Yang T, Bavley RL, Fomalont K, Blomstrom KJ, Mitz AR, Turchi J, Rudebeck PH, Murray EA (2014) Contributions of the hippocampus and entorhinal cortex to rapid visuomotor learning in rhesus monkeys. Hippocampus 24(9):1102–1111
Yao Z-H et al (2019) Tripchlorolide may improve spatial cognition dysfunction and synaptic plasticity after chronic cerebral hypoperfusion. Neural Plasticity 2019:1–14
Yokel RA, Mcnamara PJ (2010) Aluminium toxicokinetics: an updated minireview. Basic Clin Pharmacol Toxicol 88(4):159–167
Yuan JH et al (2017) Neuroprotection by plumbagin involves BDNF-TrkB-PI3K/Akt and ERK1/2/JNK pathways in isoflurane-induced neonatal rats. J Pharm Pharmacol 69(7):896–906
Zhang QL, Li MQ, Ji JW, Gao FP, Bai R, Chen CY, Wang ZW, Zhang C, Niu Q (2011) In vivo toxicity of nano-alumina on mice neurobehavioral profiles and the potential mechanisms. Int J Immunopathol Pharmacol 24(1 Suppl):23S–29S
Zhang H, Yang X, Qin X, Niu Q (2016) Caspase-3 is involved in aluminum-induced impairment of long-term potentiation in rats through the Akt/GSK-3β pathway. Neurotox Res 29(4):484–494
Zhu B, Luo L, Moore GR, Paty DW, Cynader MS (2003) Dendritic and synaptic pathology in experimental autoimmune encephalomyelitis. Am J Pathol 162(5):1639–1650
Acknowledgments
We sincerely thank colleagues for their help and work on the research.
Funding
This work was supported by the National Natural Science Foundation of China (No. 81872599, 81430078).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare that they have no conflicts of interest.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Li, H., Xue, X., Li, L. et al. Aluminum-Induced Synaptic Plasticity Impairment via PI3K-Akt-mTOR Signaling Pathway. Neurotox Res 37, 996–1008 (2020). https://doi.org/10.1007/s12640-020-00165-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12640-020-00165-5