With continuing cooperation from 18 domestic and international brain banks over the last 36 years, we have analyzed the aluminum content of the temporal lobe neocortex of 511 high-quality human female brain samples from 16 diverse neurological and neurodegenerative disorders, including 2 groups of age-matched controls. Temporal lobes (Brodmann areas A20–A22) were selected for analysis because of their availability and their central role in massive information-processing operations including efferent-signal integration, cognition, and memory formation. We used the analytical technique of (i) Zeeman-type electrothermal atomic absorption spectrophotometry (ETAAS) combined with (ii) preliminary analysis from the advanced photon source (APS) hard X-ray beam (7 GeV) fluorescence raster-scanning (XRFR) spectroscopy device (undulator beam line 2-ID-E) at the Argonne National Laboratory, US Department of Energy, University of Chicago IL, USA. Neurological diseases examined were Alzheimer’s disease (AD; N = 186), ataxia Friedreich’s type (AFT; N = 6), amyotrophic lateral sclerosis (ALS; N = 16), autism spectrum disorder (ASD; N = 26), dialysis dementia syndrome (DDS; N = 27), Down’s syndrome (DS; trisomy, 21; N = 24), Huntington’s chorea (HC; N = 15), multiple infarct dementia (MID; N = 19), multiple sclerosis (MS; N = 23), Parkinson’s disease (PD; N = 27), and prion disease (PrD; N = 11) that included bovine spongiform encephalopathy (BSE; “mad cow disease”), Creutzfeldt-Jakob disease (CJD) and Gerstmann-Straussler-Sheinker syndrome (GSS), progressive multifocal leukoencephalopathy (PML; N = 11), progressive supranuclear palsy (PSP; N = 24), schizophrenia (SCZ; N = 21), a young control group (YCG; N = 22; mean age, 10.2 ± 6.1 year), and an aged control group (ACG; N = 53; mean age, 71.4 ± 9.3 year). Using ETAAS, all measurements were performed in triplicate on each tissue sample. Among these 17 common neurological conditions, we found a statistically significant trend for aluminum to be increased only in AD, DS, and DDS compared to age- and gender-matched brains from the same anatomical region. This is the largest study of aluminum concentration in the brains of human neurological and neurodegenerative disease ever undertaken. The results continue to suggest that aluminum’s association with AD, DDS, and DS brain tissues may contribute to the neuropathology of those neurological diseases but appear not to be a significant factor in other common disorders of the human brain and/or CNS.
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McLachlan DRC, Lukiw WJ, Kruck TPA (1989) New evidence for an active role of aluminum in Alzheimer’s disease. Can J Neurol Sci 16:490–497
McLachlan DRC, Lukiw WJ, Kruck TPA (1990) Aluminum altered transcription and the pathogenesis of Alzheimer’s disease. Environ Geochem Health 12:103–114. https://doi.org/10.1007/BF01734059
Martin RB (1992) Aluminum speciation in biology Ciba Foundation Symposium 169; Aluminum in Biology and Medicine A Wiley Interscience Publication John Wiley and Sons New York (1992) pp 5–25.
Lukiw WJ (1998) Aluminum and gene transcription in Alzheimer’s disease and related neurodegenerative disorders. J Trace Elem Exp Med 11:419–420
Lukiw WJ, Bazan NG (2000) Neuroinflammatory signaling upregulation in Alzheimer’s disease. Neurochem Res 25:1173–1184
Campbell A, Yang EY, Tsai-Turton M, Bondy SC (2002) Pro-inflammatory effects of aluminum in human glioblastoma cells. Brain Res 933:60–65
McLachlan DRC, Lukiw WJ, Mizzen CA, Kruck TPA (1989) Chromatin structure in Alzheimer’s disease: effect on 5′ leader sequence for NF-L gene and role of aluminum. Prog Clin Biol Res 317:1061–1075
McLachlan DRC, Kruck TPA, Lukiw WJ, Krishnan SS (1991) Would decreased aluminum ingestion reduce the incidence of Alzheimer’s disease? CMAJ 145:793–804
Lukiw WJ, Percy ME, Kruck TPA (2005) Nanomolar aluminum induces pro-inflammatory and pro-apoptotic gene expression in human brain cells in primary culture. J Inorg Biochem 99:1895–1898
Walton JR (2013) Aluminum involvement in the progression of Alzheimer’s disease. J Alzheimers Dis 35:7–43. https://doi.org/10.3233/JAD-121909
Walton JR (2014) Chronic aluminum intake causes Alzheimer’s disease: applying Sir Austin Bradford Hill’s causality criteria. J Alzheimers Dis 40:765–838. https://doi.org/10.3233/JAD-132204
Pogue AI, Lukiw WJ (2014) The mobilization of aluminum into the biosphere. Front Neurol 5:262. https://doi.org/10.3389/fneur201400262
Pogue AI, Dua P, Hill JM, Lukiw WJ (2015) Progressive inflammatory pathology in the retina of aluminum-fed 5xFAD transgenic mice. J Inorg Biochem 152:206–209. https://doi.org/10.1016/jjinorgbio201507009
Pogue AI, Jaber V, Zhao Y, Lukiw WJ (2017) Systemic inflammation in C57BL/6J mice receiving dietary aluminum sulfate; up-regulation of the pro-inflammatory cytokines IL-6 and TNFα C-reactive protein (CRP) and miRNA-146a in blood serum. J Alzheimers Dis Parkinsonism 7(6). https://doi.org/10.4172/2161-04601000403
Garza-Lombó C, Posadas Y, Quintanar L, Gonsebatt ME, Franco R (2018) Neurotoxicity linked to dysfunctional metal ion homeostasis and xenobiotic metal exposure: redox signaling and oxidative stress. Antioxid Redox Signal 28:1669–1703. https://doi.org/10.1089/ars20177272
Krishnan SS, Gillespie KA, McLachlan DRC (1972) Determination of aluminum in biological material by atomic absorption spectrophotometry. Anal Chem 44:1469–1470
Kruck TPA, Cui JG, Percy ME, Lukiw WJ (2004) Molecular shuttle chelation: the use of ascorbate desferrioxamine and Feralex-G in combination to remove nuclear bound aluminum. Cell Mol Neurobiol 24:443–459
Kandimalla R, Vallamkondu J, Corgiat EB, Gill KD (2016) Understanding aspects of aluminum exposure in Alzheimer’s disease development. Brain Pathol 26:139–154. https://doi.org/10.1111/bpa12333
Kawahara M (2016) Link between aluminum neurotoxicity and neurodegenerative disorders. Nihon Rinsho 74:1176–1185
Barbalace K. ECAl (2018); Environmental chemistry of aluminum; EnvironmentalChemistry.com, 1995-2018; https://environmentalchemistry.com/yogi/periodic/Al.html; last accessed 20 November 2018
De Boni U, Scott JW, Crapper DR (1974) Intracellular aluminum binding; a histochemical study. Histochemistry 40:31–37
Lukiw WJ, Kruck TPA, McLachlan DRC (1987) Alterations in human linker histone-DNA binding in the presence of aluminum salts in vitro and in Alzheimer's disease. Neurotoxicology 8:291–301
Lukiw WJ, Kruck TP, McLachlan DR (1989) Linker histone-DNA complexes: enhanced stability in the presence of aluminum lactate and implications for Alzheimer’s disease. FEBS Lett 253:59–62
Walker PR, LeBlanc J, Sikorska M (1989) Effects of aluminum and other cations on the structure of brain and liver chromatin. Biochemistry 28:3911–3915. https://doi.org/10.1021/bi00435a043
Crapper DR, Krishnan SS, Dalton AJ (1973) Brain aluminum distribution in Alzheimer’s disease and experimental neurofibrillary degeneration. Science 180:511–351
Lukiw WJ, LeBlanc HJ, Carver LA, McLachlan DRC, Bazan NG (1998) Run-on gene transcription in human neocortical nuclei inhibition by nanomolar aluminum and implications for neurodegenerative disease. J Mol Neurosci 11:67–78
Alexandrov PN, Zhao Y, Pogue AI, Tarr MA, Kruck TP, Percy ME, Cui JG, Lukiw WJ (2005) Synergistic effects of iron and aluminum on stress-related gene expression in primary human neural cells. J Alzheimers Dis 8:117–127
Lukiw WJ, Pogue AI (2007) Induction of specific micro RNA (miRNA) species by ROS-generating metal sulfates in primary human brain cells. J Inorg Biochem 101:1265–1269
Lukiw WJ, Zhao Y, Cui JG (2008) An NF-kB-sensitive micro RNA-146a mediated inflammatory circuit in Alzheimer disease and in stressed human-brain cells. J Biol Chem 283:31315–31322. https://doi.org/10.1074/jbcM805371200
Pogue AI, Li YY, Cui JG, Zhao Y, Kruck TPA, Percy ME, Tarr MA, Lukiw WJ (2009) Characterization of an NF-kB-regulated miRNA-146a-mediated down-regulation of complement factor H (CFH) in metal-sulfate-stressed human brain cells. J Inorg Biochem 103:1591–1595. https://doi.org/10.1016/jjinorgbio200905012
Pogue AI, Lukiw WJ (2016) Aluminum the genetic apparatus of the human CNS and Alzheimer’s disease (AD). Morphologie 100:56–64. https://doi.org/10.1016/jmorpho201601001
Pogue AI, Lukiw WJ (2016) Natural and synthetic neurotoxins in our environment: from Alzheimer’s disease (AD) to autism spectrum disorder (ASD). J Alzheimers Dis Parkinsonism 6(4). https://doi.org/10.4172/2161-0460.1000249
Bhattacharjee S, Zhao Y, Hill JM, Culicchia F, Kruck TPA, Percy ME, Pogue AI, Walton JR et al (2013) Selective accumulation of aluminum in cerebral arteries in Alzheimer’s disease (AD). J Inorg Biochem 126:35–37. https://doi.org/10.1016/jjinorgbio201305007
D'Souza SP, Vijayalaxmi KK, Naik P (2014) Assessment of genotoxicity of aluminium acetate in bone marrow male germ cells and fetal liver cells of Swiss albino mice. Mutat Res Genet Toxicol Environ Mutagen 766:16–22. https://doi.org/10.1016/jmrgentox201402006
Alexandrov PN, Zhao Y, Jones BM, Bhattacharjee S, Lukiw WJ (2013) Expression of the phagocytosis-essential protein TREM2 is down-regulated by an aluminum-induced miRNA-34a in a murine microglial cell line. J Inorg Biochem 128:267–269. https://doi.org/10.1016/jjinorgbio201305010
Alexandrov PN, Kruck TP, Lukiw WJ (2015) Nanomolar aluminum induces expression of the inflammatory systemic biomarker C-reactive protein (CRP) in human-brain microvessel endothelial cells (hBMECs). J Inorg Biochem 152:210–213. https://doi.org/10.1016/jjinorgbio201507013
Zhao Y, Bhattacharjee S, Jones BM, Dua P, Alexandrov PN, Hill JM, Lukiw WJ (2013) Regulation of TREM2 expression by an NF-кB-sensitive miRNA-34a. Neuroreport 24:318–323. https://doi.org/10.1097/WNR0b013e32835fb6b0
Alexandrov PN, Zhao Y, Jaber V, Cong L, Lukiw WJ (2017) Deficits in the proline-rich synapse-associated Shank3 protein in multiple neuropsychiatric disorders. Front Neurol 8:670. https://doi.org/10.3389/fneur201700670
Lukiw WJ, Kruck TP, McLachlan DRC (1989) Aluminum and the nucleus of nerve cells. Lancet 1:781
Lukiw WJ, Krishnan B, Wong L, Kruck TP, Bergeron C, McLachlan DRC (1992) Nuclear compartmentalization of aluminum in Alzheimer’s disease (AD). Neurobiol Aging 13:115–121
Alexandrov PN, Pogue AI, Lukiw WJ (2018) Synergism in aluminum and mercury neurotoxicity. Integr Food Nutr Metab 5:3–7. https://doi.org/10.15761/IFNM1000214
Zhao Y, Bhattacharjee S, Jones BM, Hill J, Dua P, Lukiw WJ (2014a) Regulation of neurotropic signaling by the inducible NF-kB-sensitive miRNA-125b in Alzheimer’s disease (AD) and in primary human neuronal-glial (HNG) cells. Mol Neurobiol 50:97–106. https://doi.org/10.1007/s12035-013-8595-3
Zhao Y, Hill JM, Bhattacharjee S, Percy ME, Pogue AI, Lukiw WJ (2014b) Aluminum-induced amyloidogenesis and impairment in the clearance of amyloid peptides from the central nervous system in Alzheimer’s disease. Front Neurol 5:167. https://doi.org/10.3389/fneur201400167
Clement C, Hill JM, Dua P, Culicchia F, Lukiw WJ (2016) Analysis of RNA from Alzheimer’s disease post-mortem brain tissues. Mol Neurobiol 53:1322–1328. https://doi.org/10.1007/s12035-015-9105-6
Castro P, Zaman S, Holland A (2017) Alzheimer’s disease in people with Down’s syndrome: the prospects for and the challenges of developing preventative treatments. J Neurol 264:804–813. https://doi.org/10.1007/s00415-016-8308-8
Lee NC, Chien YH, Hwu WL (2017) A review of biomarkers for Alzheimer’s disease in Down syndrome. Neurol Ther 6:69–81. https://doi.org/10.1007/s40120-017-0071-y
Zis P, Strydom A (2018) Clinical aspects and biomarkers of Alzheimer’s disease in Down syndrome. Free Radic Biol Med 114:3–9. https://doi.org/10.1016/jfreeradbiomed201708024
Mardini J, Lavergne V, Ghannoum M (2014) Aluminum transfer during dialysis: a systematic review. Int Urol Nephrol 46:1361–1365. https://doi.org/10.1007/s11255-014-0752-8
Vadakedath S, Kandi V (2017) Dialysis: a review of the mechanisms underlying complications in the management of chronic renal failure. Cureus 9(8):e1603. https://doi.org/10.7759/cureus
Walsh B, Bazan NG, Gordon WG, Lai B, Vogt S, Lukiw WJ (2005) Trace metal analysis in Alzheimer’s disease tissues using high brilliance X-Ray beams; Sixth Keele Meeting on Aluminium Department of Biology University of Aveiro PORTUGAL
Guo H, Ingolia NT, Weissman JS, Bartel DP (2010) Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 466:835–840. https://doi.org/10.1038/nature09267
Zhao Y, Cong L, Lukiw WJ (2017) Lipopolysaccharide (LPS) accumulates in neocortical neurons of Alzheimer’s disease (AD) brain and impairs transcription in human neuronal-glial primary co-cultures. Front Aging Neurosci 9:407. https://doi.org/10.3389/fnagi201700407
Zhao Y, Lukiw WJ (2018) Bacteroidetes neurotoxins and inflammatory neurodegeneration. Mol Neurobiol 55:9100–9107. https://doi.org/10.1007/s12035-018-1015-y
Bryant PL, Lukiw WJ, Gan Z, Hall RW, Butler LG (2004) High-field 196T 27Al solid-state MAS NMR of in vitro aluminated brain tissue. J Magn Reson 170:257–262
Haouas M, Taulelle F, Martineau C (2016) Recent advances in application of 27Al NMR spectroscopy to materials science. Prog Nucl Magn Reson Spectrosc 94-95:11–36. https://doi.org/10.1016/j.pnmrs.2016.01.003
McLachlan DRC, Dalton AJ, Kruck TP, Bell MY, Smith WL, Kalow W, Andrews DF (1991) Intramuscular desferrioxamine in patients with Alzheimer's disease. Lancet 337:1304–1308. PubMed PMID:1674295.
McLachlan DRC, Fraser PE, Dalton AJ (1992) Aluminum and the pathogenesis of Alzheimer's disease: a summary of evidence. Ciba Found Symp 1992:169:87–98.
Sample collection and selection, and the analytical, experimental, and statistical work in this ongoing research is dedicated: (i) to the memory of the late DRC McLachlan, BS, MD, Order of Canada, who first proposed a potential pathological connection between aluminum and Alzheimer's disease (AD) in the early 1970s, and spent 46+ years of his scientific career establishing the link between aluminum neurotoxicity and AD; and (ii) to the memory of the late Catherine Bergeron BS, MD, Chief of Neuropathology at Toronto General Hospital, and the Department of Physiology at the University of Toronto, Toronto ON, CANADA for major contributions to this work involving post-mortem brain tissue access, characterization and multi-analysis. Sincere thanks are also extended to the late Drs. JM Hill (JMH; Louisiana State University) and TPA Kruck (TPAK; University of Toronto) for helpful discussions in this research area and to F Culicchia, C Eicken, C Hebel, B Krishnan, K Navel, and L Wong for short postmortem interval (PMI) human brain tissues or extracts, independent confirmatory aluminum analysis, and bioinformatics and data interpretation, to Drs. Barry Lai and Stefan Vogt of the Advanced Photon Source (APS), Argonne National Laboratories, US Department of Energy at the University of Chicago, and to D Guillot for expert technical assistance. We would also like to sincerely thank the many neuropathologists, physicians, and researchers of Canada, Europe, the Russian Federation, and the USA for their cooperation and provision of high-quality, short postmortem interval human CNS or brain tissues for scientific analysis and study. We would like to further thank the following brain and CNS tissue banks for access to high-quality postmortem tissues and valuable analytical advice: the Autism Brain Net, Los Angeles CA, USA; the Coriell Institute for Medical Research, Camden, NJ, USA; Harvard University/McLean Hospital Tissue Center, Boston, MA, USA; Louisiana State University, New Orleans, LA, USA; the Lomonosov Institute, Moscow State University, Moscow, Russian Federation; the National Disease Research Interchange, Philadelphia, PA, USA; the National Institutes of Health NIH NeuroBioBank [including tissues obtained from the National Institute of Mental Health (NIMH), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, MD USA]; the Netherlands Brain Research Institute, Amsterdam, Netherlands; the New York State Institute for Basic Research, Staten Island NY, USA; the Oregon Health Sciences University, Portland OR, USA; the Southern Eye Bank, Metairie LA, USA; the University of California, Irvine CA, USA; the University of Kentucky Alzheimer’s disease Brain Bank, Lexington KY, USA; the University of Maryland Brain and Tissue Bank, Baltimore MD, USA; the University of Massachusetts, Worcester MA, USA; the University of Pennsylvania School of Medicine, Philadelphia PA, USA; and the University of Toronto Brain Bank, Toronto ON, Canada. Research on metal neurotoxicity, human and murine microRNAs, small non-coding RNA (sncRNA), pro-inflammatory, and pathogenic signaling involving the innate-immune response, neuroinflammation, and amyloidogenesis in AD, ASD, PrD, and in other human neurological disorders was supported through an unrestricted grant to the LSU Eye Center from Research to Prevent Blindness (RPB); the Louisiana Biotechnology Research Network (LBRN), the Alzheimer Association (Chicago IL. USA), the Canadian Institutes of Health Research (CIHR; CB, DRCM) and NIH grants NEI EY006311, NIA AG18031 and NIA AG038834 (WJL).
Research on metal neurotoxicity, human and murine microRNAs, small non-coding RNA (sncRNA), pro-inflammatory and pathogenic signaling in the Lukiw laboratory involving the innate-immune response, neuroinflammation, and amyloidogenesis in AD, ASD, PrD, and in other human neurological disorders was supported through an unrestricted grant to the LSU Eye Center from Research to Prevent Blindness (RPB); the Louisiana Biotechnology Research Network (LBRN), the Alzheimer Association and NIH grants NEI EY006311, NIA AG18031 and NIA AG038834 (WJL).
All acquisition, handling, experimental, and analytical procedures involving postmortem human brain tissues were carried out in an ethical manner in strict accordance with the ethics review board policies at brain and tissue donor institutions and at the Louisiana State University (LSU) Health Sciences Center. Informed consent from next of kin was obtained at brain and tissue donor institutions for all tissue samples prior to autopsy and donation; coded postmortem brain tissue samples (containing no personal identifying information of the donors) were obtained from the 18 brain and tissue banks listed in the Acknowledgements section above. The ethical use of postmortem human brain tissues and their analyses were also carried out in strict accordance with the Institutional Biosafety Committee and the Institutional Review Board Committee (IBC/IRBC) ethical guidelines IBC#18059 and IRBC#6774 at the LSU Health Sciences Center, New Orleans LA 70112 USA.
Conflict of Interest Statement
Declaration of interest for all authors including financial and personal relationships with other people or organizations: none. We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. The experimental and research work in this paper was funded by the LSU Eye Center from Research to Prevent Blindness (RPB), the Louisiana Biotechnology Research Network (LBRN), the National Institutes of Health (NIH), Bethesda MD, USA and the Alzheimer Association Chicago IL, USA, and was not supported by any pro- or anti-aluminum lobby or private foundation.
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The Editor-in Chief of Molecular Neurobiology has retracted this article  at the request of the corresponding author. This is because it significantly overlaps with their previous publication . Both articles report the same results and as such this article is redundant.
Walter J. Lukiw, Maire E. Percy, and Zhide Fang agree to this retraction. William J. Walsh and Yuhai Zhao do not agree to this retraction. Aileen I. Pogue, Nathan M. Sharfman, Vivian Jaber, and Wenhong Li have not responded to any correspondence from the editor/publisher about this retraction. Donald R. C. McLachlan, Catherine Bergeron, Peter N. Alexandrov, and Theodore P. A. Kruck are deceased.
 McLachlan, D.R.C., Bergeron, C., Alexandrov, P.N. et al. Mol Neurobiol (2019) 56: 1531. https://doi.org/10.1007/s12035-018-1441-x
 McLachlan, D.R.C., Alexandrov, P.N., Walsh, W.J. et al. J Alzheimers Dis Parkinsonism (2018) 8(6): 457. https://doi.org/10.4172/2161-0460.1000457
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McLachlan, D.R.C., Bergeron, C., Alexandrov, P.N. et al. RETRACTED ARTICLE: Aluminum in Neurological and Neurodegenerative Disease. Mol Neurobiol 56, 1531–1538 (2019). https://doi.org/10.1007/s12035-018-1441-x