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Pogue A.I.,Alchem Biotech | Lukiw W.J.,Alchem Biotech | Lukiw W.J.,Louisiana State University Health Sciences Center
Morphologie | Year: 2016

The genomes of eukaryotes orchestrate their expression to ensure an effective, homeostatic and functional gene signaling program, and this includes fundamentally altered patterns of transcription during aging, development, differentiation and disease. These actions constitute an extremely complex and intricate process as genetic operations such as transcription involve the very rapid translocation and polymerization of ribonucleotides using RNA polymerases, accessory transcription protein complexes and other interrelated chromatin proteins and genetic factors. As both free ribonucleotides and polymerized single-stranded RNA chains, ribonucleotides are highly charged with phosphate, and this genetic system is extremely vulnerable to disruption by a large number of electrostatic forces, and primarily by cationic metals such as aluminum. Aluminum has been shown by independent researchers to be particularly genotoxic to the genetic apparatus, and it has become reasonably clear that aluminum disturbs genetic signaling programs in the CNS that bear a surprising resemblance to those observed in Alzheimer's disease (AD) brain. This paper will focus on a discussion of two molecular-genetic aspects of aluminum genotoxicity: (1) the observation that micro-RNA (miRNA)-mediated global gene expression patterns in aluminum-treated transgenic animal models of AD (Tg-AD) strongly resemble those found in AD; and (2) the concept of "human biochemical individuality" and the hypothesis that individuals with certain gene expression patterns may be especially sensitive and perhaps predisposed to aluminum genotoxicity. © 2016 Elsevier Masson SAS. Source


AI P.,Alchem Biotech | P D.,Louisiana State University | JM H.,Louisiana State University Health Sciences Center | WJ L.,Louisiana State University Health Sciences Center
Journal of Inorganic Biochemistry | Year: 2015

At least 57 murine transgenic models for Alzheimer's disease (Tg-AD) have been developed to overexpress the 42 amino acid amyloid-beta (Aβ42) peptide in the central nervous system (CNS). These '. humanized murine Tg-AD models' have greatly expanded our understanding of the contribution of Aβ42 peptide-mediated pro-inflammatory neuropathology to the AD process. A number of independent laboratories using different amyloid-overexpressing Tg-AD models have shown that supplementation of murine Tg-AD diets and/or drinking water with aluminum significantly enhances Aβ42 peptide-mediated inflammatory pathology and AD-type cognitive change compared to animals receiving control diets. In humans AD-type pathology appears to originate in the limbic system and progressively spreads into primary processing and sensory regions such as the retina. In these studies, for the first time, we assess the propagation of Aβ42 and inflammatory signals into the retina of 5xFAD Tg-AD amyloid-overexpressing mice whose diets were supplemented with aluminum. The two most interesting findings were (1) that similar to other Tg-AD models, there was a significantly accelerated development of Aβ42 and inflammatory pathology in 5xFAD Tg-AD mice fed aluminum; and (2) in aluminum-supplemented animals, markers for inflammatory pathology appeared in both the brain and the retina as evidenced by an evolving presence of Aβ42 peptides, and accompanied by inflammatory markers - cyclooxygenase-2 (COX-2) and C-reactive protein (CRP). The results indicate that in the 5xFAD Tg-AD model aluminum not only enhances an Aβ42-mediated inflammatory degeneration of the brain but also appears to induce AD-type pathology in an anatomically-linked primary sensory area that involves vision. © 2015. Source


Zhao Y.,Louisiana State University Health Sciences Center | Hill J.M.,Louisiana State University Health Sciences Center | Bhattacharjee S.,Louisiana State University Health Sciences Center | Percy M.E.,University of Toronto | And 3 more authors.
Frontiers in Neurology | Year: 2014

The membrane-integral beta amyloid precursor protein (βAPP) is probably the most intensively studied brain cell protein in all of neurobiology. βAPP is processed by tandem beta-gamma secretase cleavage into 42 amino acid amyloid (Aβ42) peptides whose progressive accumulation is one distinguishing feature of Alzheimer's disease (AD) neuropathology [1-3]. While homeostatic amounts of Aβ42 peptide generation and clearance seem to be tolerated by brain cells, their over-abundance, aggregation into higher order structures and inability of brain cells to effectively phagocytose and clear these intensely hydrophobic peptides contributes to the pro-inflammatory and neurotoxic pathology of AD. Aluminum, as an extremely high charge density cation (Z2/r=18) has the remarkable capability to both (1) aggregate and compact Aβ42 peptide monomers into higher order, more neurotoxic oligomeric and fibrillar structures, and (2) impair, at the molecular-genetic level, the cellular machinery responsible for Aβ42 peptide monomer phagocytosis and clearance from the cell [4-13]. This opinion paper will briefly assess these two remarkable, functionally overlapping, and decidedly neurotoxic properties of aluminum - (1) on the ability of physiologically realistic amounts of aluminum to aggregate Aβ42 peptide monomers into higher order dimeric, oligomeric and fibrillar structures, and (2) on the ability of aluminum to impair, at nanomolar concentrations and at the level of epigenetic regulation, microglial cell-mediated clearance mechanisms of Aβ42 peptides from the extracellular space of the brain and CNS. © 2014 Zhao, Hill, Bhattacharjee, Percy, Pogue and Lukiw. Source


Bhattacharjee S.,Neuroscience Center | Zhao Y.,Neuroscience Center | Hill J.M.,Neuroscience Center | Hill J.M.,Louisiana State University Health Sciences Center | And 8 more authors.
Journal of Inorganic Biochemistry | Year: 2013

Once biologically available aluminum bypasses gastrointestinal and blood-brain barriers, this environmentallyabundant neurotoxin has an exceedingly high affinity for the large pyramidal neurons of the human brain hippocampus. This same anatomical region of the brain is also targeted by the earliest evidence of Alzheimer's disease (AD) neuropathology. Themechanismfor the selective targeting and transport of aluminuminto the hippocampus of the human brain is notwell understood. In an effort to improve our understanding of a pathological aluminumentry systeminto the brain, this study examined the aluminumcontent of 8 arteries that supply blood to the hippocampus, including the aorta and several cerebral arteries. In contrast to age-matched controls, in AD patients we found a gradient of increasing aluminum concentration from the aorta to the posterior cerebral artery that supplies blood to the hippocampus. Primary cultures of human brain endothelial cells were found to have an extremely high affinity for aluminum when compared to other types of brain cells. Together, these results suggest for the first time that endothelial cells that line the cerebral vasculature may have biochemical attributes conducive to binding and targeting aluminum to selective anatomical regions of the brain, such as the hippocampus, with potential downstream pro-inflammatory and pathogenic consequences. © 2013 Elsevier Inc. Source


Pogue A.,Alchem Biotech | Dua P.P.,Louisiana State University | Hill J.,Louisiana State University Health Sciences Center | Lukiw W.,Alchem Biotech | Lukiw W.,Louisiana State University Health Sciences Center
Journal of Inorganic Biochemistry | Year: 2015

At least 57 murine transgenic models for Alzheimer's disease (Tg-AD) have been developed to overexpress the 42 amino acid amyloid-beta (Aβ42) peptide in the central nervous system (CNS). These 'humanized murine Tg-AD models' have greatly expanded our understanding of the contribution of Aβ42 peptide-mediated pro-inflammatory neuropathology to the AD process. A number of independent laboratories using different amyloid-overexpressing Tg-AD models have shown that supplementation of murine Tg-AD diets and/or drinking water with aluminum significantly enhances Aβ42 peptide-mediated inflammatory pathology and AD-type cognitive change compared to animals receiving control diets. In humans AD-type pathology appears to originate in the limbic system and progressively spreads into primary processing and sensory regions such as the retina. In these studies, for the first time, we assess the propagation of Aβ42 and inflammatory signals into the retina of 5xFAD Tg-AD amyloid-overexpressing mice whose diets were supplemented with aluminum. The two most interesting findings were (1) that similar to other Tg-AD models, there was a significantly accelerated development of Aβ42 and inflammatory pathology in 5xFAD Tg-AD mice fed aluminum; and (2) in aluminum-supplemented animals, markers for inflammatory pathology appeared in both the brain and the retina as evidenced by an evolving presence of Aβ42 peptides, and accompanied by inflammatory markers - cyclooxygenase-2 (COX-2) and C-reactive protein (CRP). The results indicate that in the 5xFAD Tg-AD model aluminum not only enhances an Aβ42-mediated inflammatory degeneration of the brain but also appears to induce AD-type pathology in an anatomically-linked primary sensory area that involves vision. © 2015 Elsevier Inc. All rights reserved. Source

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