Skip to main content

Advertisement

Log in

Local and Systemic Hypoxia as Inductors of Increased Aluminum and Iron Brain Accumulation Promoting the Onset of Alzheimer’s Disease

  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

Data Availability

N/A.

Materials availability

N/A.

References

  1. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Jankovic J, Mazziotta JC, Pomeroy SL (2021) Bradley's neurology in clinical practice e-book 7th ed Elsevier Health Sci

  3. 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

    Google Scholar 

  4. Jurcovicova J (2014) Glucose transport in brain - effect of inflammation. Endocr Regul 48:35–48

    Article  CAS  PubMed  Google Scholar 

  5. 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

    Article  CAS  PubMed  Google Scholar 

  6. 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

  7. Mladenovic J (1988) Aluminum inhibits erythropoiesis in vitro. J Clin Investig 81:1661–1665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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

    Article  CAS  PubMed  Google Scholar 

  9. 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

    Chapter  Google Scholar 

  10. Kumar V, Gill KD (2014) Oxidative stress and mitochondrial dysfunction in aluminium neurotoxicity and its amelioration: a review. Neurotoxicology 41:154–166

    Article  CAS  PubMed  Google Scholar 

  11. 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

    Article  CAS  PubMed  Google Scholar 

  12. 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

  13. 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

    Article  Google Scholar 

  14. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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

    Article  CAS  PubMed  Google Scholar 

  16. 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

    Article  Google Scholar 

  17. 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

    Article  CAS  PubMed  Google Scholar 

  18. 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

    Article  PubMed  Google Scholar 

  19. 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

    Article  CAS  PubMed  Google Scholar 

  20. 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

    Article  CAS  PubMed  Google Scholar 

  21. Zhao Z (2019) Iron and oxidizing species in oxidative stress and Alzheimer’s disease. Aging Med (Milton (N.S.W)) 2:82–87

  22. 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

    Article  CAS  PubMed  Google Scholar 

  23. 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

    CAS  PubMed  Google Scholar 

  24. 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

    Article  CAS  PubMed  Google Scholar 

  25. 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

    Article  CAS  PubMed  Google Scholar 

  26. 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

    Article  CAS  PubMed  Google Scholar 

  27. Baylor NW, Egan W, Richman P (2002) Aluminum salts in vaccines—US perspective. Vaccine 20:S18–S23

    Article  CAS  PubMed  Google Scholar 

  28. Burrell SA, Exley C (2010) There is (still) too much aluminium in infant formulas. BMC Pediatr 10:63

    Article  PubMed  PubMed Central  Google Scholar 

  29. 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

    Article  PubMed  Google Scholar 

  30. 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

    Article  PubMed  Google Scholar 

  31. Borowska S, Brzóska MM (2015) Metals in cosmetics: implications for human health. J Appl Toxicol : JAT 35:551–572

    Article  CAS  PubMed  Google Scholar 

  32. Reinke CM, Breitkreutz J, Leuenberger H (2003) Aluminium in over-the-counter drugs: risks outweigh benefits? Drug Saf 26:1011–1025

    Article  CAS  PubMed  Google Scholar 

  33. 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

    Article  CAS  Google Scholar 

  34. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Exley C (2014) Aluminium adjuvants and adverse events in sub-cutaneous allergy immunotherapy. Allergy Asthma Clin Immunol 10:4–4

    Article  PubMed  PubMed Central  Google Scholar 

  36. 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

    Article  PubMed  PubMed Central  Google Scholar 

  37. 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

    Article  CAS  PubMed  Google Scholar 

  38. 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

    Article  CAS  PubMed  Google Scholar 

  39. 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

    Article  CAS  Google Scholar 

  40. Trapp GA (1983) Plasma aluminum is bound to transferrin. Life Sci 33:311–316

    Article  CAS  PubMed  Google Scholar 

  41. 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

    Article  CAS  Google Scholar 

  42. Wang L (2018) Entry and deposit of aluminum in the brain. Adv Exp Med Biol 1091:39–51

    Article  CAS  PubMed  Google Scholar 

  43. 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

    Article  CAS  PubMed  Google Scholar 

  44. Exley C, Mold MJ (2019) Aluminium in human brain tissue: how much is too much? J Biol Inorg Chem 24:1279–1282

    Article  CAS  PubMed  Google Scholar 

  45. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 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

    Article  PubMed  Google Scholar 

  47. 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

    Article  CAS  PubMed  Google Scholar 

  48. 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

    Article  CAS  PubMed  Google Scholar 

  49. 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

  50. 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

    Article  Google Scholar 

  51. Scott CW, Fieles A, Sygowski LA, Caputo CB (1993) Aggregation of tau protein by aluminum. Brain Res 628:77–84

    Article  CAS  PubMed  Google Scholar 

  52. 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

    Article  CAS  Google Scholar 

  53. 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

    Article  CAS  PubMed  Google Scholar 

  54. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. 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

    Article  CAS  PubMed  Google Scholar 

  57. Lok CN, Ponka P (1999) Identification of a hypoxia response element in the transferrin receptor gene. J Biol Chem 274:24147–24152

    Article  CAS  PubMed  Google Scholar 

  58. Xiang J (2017) Carotid atherosclerosis promotes the progression of Alzheimer’s disease: a three-year prospective study. Exp Ther Med 14:1321–1326

    Article  PubMed  PubMed Central  Google Scholar 

  59. 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

    Article  CAS  PubMed  Google Scholar 

  60. 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

    Article  CAS  PubMed  Google Scholar 

  61. 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

    Article  CAS  Google Scholar 

  62. 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

    Article  PubMed  PubMed Central  Google Scholar 

  63. 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

    Article  CAS  PubMed  Google Scholar 

  64. 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

    Article  CAS  PubMed  Google Scholar 

  65. 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

    Article  CAS  Google Scholar 

  66. 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

    Article  PubMed  Google Scholar 

  67. 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

    Article  PubMed  PubMed Central  Google Scholar 

  68. 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

    Article  PubMed  PubMed Central  Google Scholar 

  69. 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

    Article  PubMed  PubMed Central  Google Scholar 

  70. 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

    Article  PubMed  Google Scholar 

  71. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. 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

    Article  Google Scholar 

  73. 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

    CAS  Google Scholar 

  74. 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

    Article  PubMed  PubMed Central  Google Scholar 

  75. 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

    Article  CAS  PubMed  Google Scholar 

  76. Hassan H, Chen R (2021) Hypoxia in Alzheimer’s disease: effects of hypoxia inducible factors. Neural Regen Res 16:310–311

    Article  CAS  PubMed  Google Scholar 

  77. Ashok BS, Ajith TA, Sivanesan S (2017) Hypoxia-inducible factors as neuroprotective agent in Alzheimer’s disease. Clin Exp Pharmacol Physiol 44:327–334

    Article  CAS  PubMed  Google Scholar 

  78. 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

    Article  CAS  PubMed  Google Scholar 

  79. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

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

Correspondence to Aleksandar Cirovic.

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.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12011-023-03599-y

Keywords

Navigation