Abstract
Human environment is highly contaminated with aluminum, and aluminum is toxic to majority of tissues, particularly to neurons. In previous decades, aluminum exposure was frequently linked with the onset of Alzheimer’s disease (AD), and increased levels of Al were detected in the brains of individuals with AD. People who live in a certain area are exposed to aluminum in a similar way (they eat the same vegetable and other foodstuffs, use similar cosmetics, and buy medications from the same manufacturer), nevertheless not all of them develop Alzheimer’s disease. Majority of known risk factors for AD promote atherosclerosis and consequently reduce brain blood supply. In this review, we highlighted the significance of local (carotid disease and atherosclerosis of intracranial blood vessels) and systemic hypoxia (chronic obstructive pulmonary disease and anemia) in the development of AD. Nerve tissue is very sophisticated and sensitive to hypoxia and aluminum toxicity. As a side effect of compensatory mechanisms in case of hypoxia, neurons start to uptake aluminum and iron to a greater extent. This makes perfect a background for the gradual onset and development of AD.
Similar content being viewed by others
Data Availability
N/A.
Materials availability
N/A.
References
Plassman BL, Langa KM, Fisher GG, Heeringa SG, Weir DR, Ofstedal MB, Burke JR, Hurd MD, Potter GG, Rodgers WL (2007) Prevalence of dementia in the United States: the aging, demographics, and memory study. Neuroepidemiology 29:125–132
Jankovic J, Mazziotta JC, Pomeroy SL (2021) Bradley's neurology in clinical practice e-book 7th ed Elsevier Health Sci
Hong CH, Falvey C, Harris TB, Simonsick EM, Satterfield S, Ferrucci L, Metti AL, Patel KV, Yaffe K (2013) Anemia and risk of dementia in older adults. Find Health ABC Stud 81:528–533
Jurcovicova J (2014) Glucose transport in brain - effect of inflammation. Endocr Regul 48:35–48
Fernandes RM, Corrêa MG, Aragão WAB, Nascimento PC, Cartágenes SC, Rodrigues CA, Sarmiento LF, Monteiro MC, Maia C, Crespo-López ME, Lima RR (2020) Preclinical evidences of aluminum-induced neurotoxicity in hippocampus and pre-frontal cortex of rats exposed to low doses. Ecotoxicol Environ Saf 206:111139
Souza-Monteiro D, Ferreira RO, Eiró LG, de Oliveira Lima LA, Balbinot GS, da Paz SPA, Albuquerque ARL, Collares FM, Angélica RS, Pessanha S, do Socorro Ferraz Maia C, Lima RR (2021) Long-term exposure to low doses of aluminum affects mineral content and microarchitecture of rats alveolar bone. Environ Sci Pollut Res Int 28:45879-45890
Mladenovic J (1988) Aluminum inhibits erythropoiesis in vitro. J Clin Investig 81:1661–1665
Yuan CY, Lee YJ, Hsu GS (2012) Aluminum overload increases oxidative stress in four functional brain areas of neonatal rats. J Biomed Sci 19:51
Fernandes RM, Eiró LG, Chemelo VdS, Alvarenga MOP, Lima RR (2021) Chapter 14 - aluminum toxicity and oxidative stress. In: Patel VB, Preedy VR (eds) Toxicology. Academic Press, pp 127–135
Kumar V, Gill KD (2014) Oxidative stress and mitochondrial dysfunction in aluminium neurotoxicity and its amelioration: a review. Neurotoxicology 41:154–166
Liu H, Zhang W, Fang Y, Yang H, Tian L, Li K, Lai W, Bian L, Lin B, Liu X, Xi Z (2020) Neurotoxicity of aluminum oxide nanoparticles and their mechanistic role in dopaminergic neuron injury involving p53-related pathways. J Hazard Mater 392:122312
de Lima WF, Né YGS, Aragão WAB, Eiró-Quirino L, Baia-da-Silva DC, Cirovic A, Cirovic A, Lima RR (2022) Global scientific research landscape on aluminum toxicology. Biol Trace Elem Res 1–15
Yuan C-Y, Lee Y-J, Hsu G-SW (2012) Aluminum overload increases oxidative stress in four functional brain areas of neonatal rats. J Biomed Sci 19:1–9
Bittencourt LO, Damasceno-Silva RD, Aragão WAB, Eiró-Quirino L, Oliveira ACA, Fernandes RM, Freire MAM, Cartágenes SC, Dionizio A, Buzalaf MAR, Cassoli JS, Cirovic A, Cirovic A, Maia CdSF, Lima RR (2022) Global proteomic profile of aluminum-induced hippocampal impairments in rats: are low doses of aluminum really safe? Int J Mol Sci 23:12523
Cheng L, Liang R, Li Z, Ren J, Yang S, Bai J, Niu Q, Yu H, Zhang H, Xia N, Liu H (2021) Aluminum maltolate triggers ferroptosis in neurons: mechanism of action. Toxicol Mech Methods 31:33–42
Ćirović A, Ćirović A, Nikolić D, Ivanovski A, Ivanovski P (2021) The adjuvant aluminum fate - metabolic tale based on the basics of chemistry and biochemistry. J Trace Elem Med Biol : Organ Soc Miner Trace Elem 68:126822
Platt B, Drysdale AJ, Nday C, Roloff E, Drever BD, Salifoglou A (2007) Differential toxicity of novel aluminium compounds in hippocampal culture. Neurotoxicology 28:576–586
Suárez-Fernández MB, Soldado AB, Sanz-Medel A, Vega JA, Novelli A, Fernández-Sánchez MT (1999) Aluminum-induced degeneration of astrocytes occurs via apoptosis and results in neuronal death. Brain Res 835:125–136
Campbell A, Hamai D, Bondy SC (2001) Differential toxicity of aluminum salts in human cell lines of neural origin: implications for neurodegeneration. Neurotoxicology 22:63–71
Song Y, Xue Y, Liu X, Wang P, Liu L (2008) Effects of acute exposure to aluminum on blood-brain barrier and the protection of zinc. Neurosci Lett 445:42–46
Zhao Z (2019) Iron and oxidizing species in oxidative stress and Alzheimer’s disease. Aging Med (Milton (N.S.W)) 2:82–87
Jena BS, Nayak SB, Patnaik BK (2002) Age-related effect of aluminium on the catalase activities of the brains of two species of poikilothermic vertebrates. Gerontology 48:34–38
Chainy GB, Samanta L, Rout NB (1996) Effect of aluminum on superoxide dismutase, catalase and lipid peroxidation of rat liver. Res Commun Mol Pathol Pharmacol 94:217–220
Silva VS, Gonçalves PP (2003) The inhibitory effect of aluminium on the (Na+/K+)ATPase activity of rat brain cortex synaptosomes. J Inorg Biochem 97:143–150
Zatta P, Lain E, Cagnolini C (2000) Effects of aluminum on activity of Krebs cycle enzymes and glutamate dehydrogenase in rat brain homogenate. Eur J Biochem 267:3049–3055
Zhang J, Huang W, Xu F, Cao Z, Jia F, Li Y (2020) Iron dyshomeostasis participated in rat hippocampus toxicity caused by aluminum chloride. Biol Trace Elem Res 197:580–590
Baylor NW, Egan W, Richman P (2002) Aluminum salts in vaccines—US perspective. Vaccine 20:S18–S23
Burrell SA, Exley C (2010) There is (still) too much aluminium in infant formulas. BMC Pediatr 10:63
El Daouk S, Pineau A, Taha M, Ezzeddine R, Hijazi A, Al Iskandarani M (2020) Aluminum exposure from food in the population of Lebanon. Toxicol Rep 7:1025–1031
Van Dyke N, Yenugadhati N, Birkett NJ, Lindsay J, Turner MC, Willhite CC, Krewski D (2021) Association between aluminum in drinking water and incident Alzheimer’s disease in the Canadian Study of Health and Aging cohort. Neurotoxicology 83:157–165
Borowska S, Brzóska MM (2015) Metals in cosmetics: implications for human health. J Appl Toxicol : JAT 35:551–572
Reinke CM, Breitkreutz J, Leuenberger H (2003) Aluminium in over-the-counter drugs: risks outweigh benefits? Drug Saf 26:1011–1025
Filippini T, Tancredi S, Malagoli C, Cilloni S, Malavolti M, Violi F, Vescovi L, Bargellini A, Vinceti M (2019) Aluminum and tin: food contamination and dietary intake in an Italian population. J Trace Elem Med Biol : Organ Soc Miner Trace Elem 52:293–301
Wang B, Liu Y, Wang H, Cui L, Zhang Z, Guo J, Liu S, Cui W (2020) Contamination and health risk assessment of lead, arsenic, cadmium, and aluminum from a total diet study of Jilin Province, China. Food Sci Nutr 8:5631–5640
Exley C (2014) Aluminium adjuvants and adverse events in sub-cutaneous allergy immunotherapy. Allergy Asthma Clin Immunol 10:4–4
Ogawa M, Kayama F (2015) A study of the association between urinary aluminum concentration and pre-clinical findings among aluminum-handling and non-handling workers. J Occup Med Toxicol 10:13
Hao W, Hao C, Wu C, Xu Y, Jin C (2022) Aluminum induced intestinal dysfunction via mechanical, immune, chemical and biological barriers. Chemosphere 288:132556
Priest ND, Skybakmoen E, Jackson G (2021) The bioavailability of ingested (26)Al-labelled aluminium and aluminium compounds in the rat. Neurotoxicology 83:179–185
Day JP, Barker J, Evans LJA, Perks J, Seabright PJ, Ackrill P, Lilley JS, Drumm PV, Newton GWA (1991) Aluminium absorption studied by 26Al tracer. The Lancet 337:1345
Trapp GA (1983) Plasma aluminum is bound to transferrin. Life Sci 33:311–316
Jouhanneau P, Raisbeck GM, Yiou F, Lacour B, Banide H, Drüeke TB (1997) Gastrointestinal absorption, tissue retention, and urinary excretion of dietary aluminum in rats determined by using 26Al. Clin Chem 43:1023–1028
Wang L (2018) Entry and deposit of aluminum in the brain. Adv Exp Med Biol 1091:39–51
Mold M, Linhart C, Gómez-Ramírez J, Villegas-Lanau A, Exley C (2020) Aluminum and amyloid-β in familial Alzheimer’s disease. J Alzheimers Dis : JAD 73:1627–1635
Exley C, Mold MJ (2019) Aluminium in human brain tissue: how much is too much? J Biol Inorg Chem 24:1279–1282
Exley C, Clarkson E (2020) Aluminium in human brain tissue from donors without neurodegenerative disease: a comparison with Alzheimer’s disease, multiple sclerosis and autism. Sci Rep 10:7770
Andrási E, Páli N, Molnár Z, Kösel S (2005) Brain aluminum, magnesium and phosphorus contents of control and Alzheimer-diseased patients. J Alzheimers Dis 7:273–284
Yumoto S, Kakimi S, Ishikawa A (2018) Colocalization of aluminum and iron in nuclei of nerve cells in brains of patients with Alzheimer’s disease. J Alzheimers Dis : JAD 65:1267–1281
Du L, Zhao Z, Cui A, Zhu Y, Zhang L, Liu J, Shi S, Fu C, Han X, Gao W, Song T, Xie L, Wang L, Sun S, Guo R, Ma G (2018) Increased iron deposition on brain quantitative susceptibility mapping correlates with decreased cognitive function in Alzheimer’s disease. ACS Chem Neurosci 9:1849–1857
Drochioiu G, Murariu M, Ion L, Habasescu L (2014) Iron and aluminum interaction with amyloid-beta peptides associated with Alzheimer’s disease. In: AIP Conf Proc Am Inst Phys 1618(1):99–100
Liu JL, Fan YG, Yang ZS, Wang ZY, Guo C (2018) Iron and Alzheimer’s disease: from pathogenesis to therapeutic implications. Front Neurosci 10(12):632
Scott CW, Fieles A, Sygowski LA, Caputo CB (1993) Aggregation of tau protein by aluminum. Brain Res 628:77–84
Lin C, McGough R, Aswad B, Block JA, Terek R (2004) Hypoxia induces HIF-1alpha and VEGF expression in chondrosarcoma cells and chondrocytes. J Orthop Res : Off Publ Orthop Res Soc 22:1175–1181
Qian ZM, Wu XM, Fan M, Yang L, Du F, Yung WH, Ke Y (2011) Divalent metal transporter 1 is a hypoxia-inducible gene. J Cell Physiol 226:1596–1603
Nicolas G, Chauvet C, Viatte L, Danan JL, Bigard X, Devaux I, Beaumont C, Kahn A, Vaulont S (2002) The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Investig 110:1037–1044
Bianchi L, Tacchini L, Cairo G (1999) HIF-1-mediated activation of transferrin receptor gene transcription by iron chelation. Nucleic Acids Res 27:4223–4227
Tacchini L, Bianchi L, Bernelli-Zazzera A, Cairo G (1999) Transferrin receptor induction by hypoxia. HIF-1-mediated transcriptional activation and cell-specific post-transcriptional regulation. J Biol Chem 274:24142–24146
Lok CN, Ponka P (1999) Identification of a hypoxia response element in the transferrin receptor gene. J Biol Chem 274:24147–24152
Xiang J (2017) Carotid atherosclerosis promotes the progression of Alzheimer’s disease: a three-year prospective study. Exp Ther Med 14:1321–1326
Kitaguchi H, Tomimoto H, Ihara M, Shibata M, Uemura K, Kalaria RN, Kihara T, Asada-Utsugi M, Kinoshita A, Takahashi R (2009) Chronic cerebral hypoperfusion accelerates amyloid β deposition in APPSwInd transgenic mice. Brain Res 1294:202–210
Kitaguchi H, Tomimoto H, Ihara M, Shibata M, Uemura K, Kalaria RN, Kihara T, Asada-Utsugi M, Kinoshita A, Takahashi R (2009) Chronic cerebral hypoperfusion accelerates amyloid beta deposition in APPSwInd transgenic mice. Brain Res 1294:202–210
Bannai T, Mano T, Chen X, Ohtomo G, Ohtomo R, Tsuchida T, Koshi-Mano K, Hashimoto T, Okazawa H, Iwatsubo T (2019) Chronic cerebral hypoperfusion shifts the equilibrium of amyloid β oligomers to aggregation-prone species with higher molecular weight. Sci Rep 9:1–11
Bannai T, Mano T, Chen X, Ohtomo G, Ohtomo R, Tsuchida T, Koshi-Mano K, Hashimoto T, Okazawa H, Iwatsubo T, Tsuji S, Toda T, Iwata A (2019) Chronic cerebral hypoperfusion shifts the equilibrium of amyloid β oligomers to aggregation-prone species with higher molecular weight. Sci Rep 9:2827
Okamoto Y, Yamamoto T, Kalaria RN, Senzaki H, Maki T, Hase Y, Kitamura A, Washida K, Yamada M, Ito H, Tomimoto H, Takahashi R, Ihara M (2012) Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts. Acta Neuropathol 123:381–394
Kazim SF, Sharma A, Saroja SR, Seo JH, Larson CS, Ramakrishnan A, Wang M, Blitzer RD, Shen L, Peña CJ, Crary JF, Shimoda LA, Zhang B, Nestler EJ, Pereira AC (2022) Chronic intermittent hypoxia enhances pathological tau seeding, propagation, and accumulation and exacerbates Alzheimer-like memory and synaptic plasticity deficits and molecular signatures. Biol Psychiat 91:346–358
Cirovic A, Cirovic A (2022) Aluminum bone toxicity in infants may be promoted by iron deficiency. J Trace Elem Med Biol : Organ Soc Miner Trace Elem 71:126941
Liao K-M, Ho C-H, Ko S-C, Li C-Y (2015) Increased risk of dementia in patients with chronic obstructive pulmonary disease. Medicine (Baltimore) 94:e930–e930
Lutsey PL, Chen N, Mirabelli MC, Lakshminarayan K, Knopman DS, Vossel KA, Gottesman RF, Mosley TH, Alonso A (2019) Impaired lung function, lung disease, and risk of incident dementia. Am J Respir Crit Care Med 199:1385–1396
Alexandre F, Heraud N, Sanchez AMJ, Tremey E, Oliver N, Guerin P, Varray A (2016) Brain damage and motor cortex impairment in chronic obstructive pulmonary disease: implication of nonrapid eye movement sleep desaturation. Sleep 39:327–335
Hong CH, Falvey C, Harris TB, Simonsick EM, Satterfield S, Ferrucci L, Metti AL, Patel KV, Yaffe K (2013) Anemia and risk of dementia in older adults: findings from the health ABC study. Neurology 81:528–533
Chen YG, Lin TY, Chen HJ, Dai MS, Ho CL, Kao CH (2015) Thalassemia and risk of dementia: a nationwide population-based retrospective cohort study. Eur J Intern Med 26:554–559
Wolters FJ, Zonneveld HI, Licher S, Cremers LGM, Heart Brain Connection Collaborative Research G, Ikram MK, Koudstaal PJ, Vernooij MW, Ikram MA (2019) Hemoglobin and anemia in relation to dementia risk and accompanying changes on brain MRI. Neurology 93:e917–e926
Albayrak L, Türksoy VA, Khalilov R, Eftekhari A (2023) Investigation of heavy metal exposure and trace element levels in acute exacerbatıon of COPD. J King Saud Univ - Sci 35:102422
Zhang T, He F, Lin S, Wang X, Li F, Zhai Y, Gu X, Wu M, Lin J (2021) Does aluminum exposure affect cognitive function? Comp Cross-Sectional Stud 16:e0246560
Lin S-Y, Hsu W-H, Lin C-C, Lin C-L, Yeh H-C, Kao C-H (2019) Association of transfusion with risks of dementia or Alzheimer’s disease: a population-based cohort study. Front Psychiatry 10:571–571
Connor JR, Milward EA, Moalem S, Sampietro M, Boyer P, Percy ME, Vergani C, Scott RJ, Chorney M (2001) Is hemochromatosis a risk factor for Alzheimer’s disease? J Alzheimers Dis : JAD 3:471–477
Hassan H, Chen R (2021) Hypoxia in Alzheimer’s disease: effects of hypoxia inducible factors. Neural Regen Res 16:310–311
Ashok BS, Ajith TA, Sivanesan S (2017) Hypoxia-inducible factors as neuroprotective agent in Alzheimer’s disease. Clin Exp Pharmacol Physiol 44:327–334
Wang Y-Y, Huang Z-T, Yuan M-H, Jing F, Cai R-L, Zou Q, Pu Y-S, Wang S-Y, Chen F, Yi W-M (2021) Role of hypoxia inducible factor-1α in Alzheimer’s disease. J Alzheimers Dis 80:949–961
Merelli A, Rodríguez JCG, Folch J, Regueiro MR, Camins A, Lazarowski A (2018) Understanding the role of hypoxia inducible factor during neurodegeneration for new therapeutics opportunities. Curr Neuropharmacol 16:1484–1498
Chai X, Kong W, Liu L, Yu W, Zhang Z, Sun Y (2014) A viral vector expressing hypoxia-inducible factor 1 alpha inhibits hippocampal neuronal apoptosis. Neural Regen Res 9:1145–1153
Author information
Authors and Affiliations
Contributions
Conceptualization: Aleksandar Cirovic; literature search: Ana Cirovic; writing—original draft: Ana Cirovic and Aleksandar Cirovic; critically revised the work: Orish E Orisakwea and Rafael Rodrigues Lima; validation: all the authors.
Corresponding author
Ethics declarations
Ethical Approval
N/A.
Consent to Participate
N/A.
Consent for Publication
N/A.
Competing Interests
The authors declare no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Cirovic, A., Cirovic, A., Orisakwe, O.E. et al. Local and Systemic Hypoxia as Inductors of Increased Aluminum and Iron Brain Accumulation Promoting the Onset of Alzheimer’s Disease. Biol Trace Elem Res 201, 5134–5142 (2023). https://doi.org/10.1007/s12011-023-03599-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12011-023-03599-y