Linker histone‐DNA complexes: enhanced stability in the presence of aluminum lactate and implications for Alzheimer's disease

Lukiw, Walter J.; Kruck, Theo P.A.; McLachlan, Donald R.

doi:10.1016/0014-5793(89)80929-9

Cited by 25 publications

(10 citation statements)

References 20 publications

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“…Repeated chelation therapy with DFO in 26 Al-treated rats shows that some Al persists in the brain for a long time (half-life of brain 26 Al was estimated to be 150 and 55 days in the control and DFO-treated group respectively) [68]. These data indicate that Al is tightly bound to intracellular pools and are consistent with frequent observations of perinuclear and nuclear foci of Al in AD brains [10,42,47,59,182,185].…”

Section: Aluminum Toxicokinetics Across the Brain Barriers: More Thansupporting

confidence: 80%

“…Once in the brain ECF, Al will either bind to polar headgroups of membrane phospholipids, or enter intracellular pools, most probably via transferrin uptake, monocarboxylate transporter (MCT) -and/or organic anion transporter-mediated mechanisms [6,27,68,152,175]. Endoplasmic reticulum (ER), nuclear chromatin, hyperphosphorylated tau, and ATP are believed to be the major binding targets of intracellular Al [6,174,[182][183][184]. Repeated chelation therapy with DFO in 26 Al-treated rats shows that some Al persists in the brain for a long time (half-life of brain 26 Al was estimated to be 150 and 55 days in the control and DFO-treated group respectively) [68].…”

Section: Aluminum Toxicokinetics Across the Brain Barriers: More Thanmentioning

confidence: 99%

“…At nanomolar concentrations, Al inhibits brain-specific gene transcription from selected AT-rich promoters of human neocortical genes [155]. Al repressive action on gene transcription is linked to its ability to: 1) decrease the access of transcriptional machinery to initiation sites on DNA template by enhancing chromatin condensation [174,[182][183][184][185], 2) interfere with ATP-hydrolysis-powered separation of DNA strands either indirectly (by binding to phosphonucleotides and increasing the stability and melting temperature of DNA) [155,236] or directly (by inhibiting the ATPase-dependent action of RNA polymerase) [155]. These effects were experimentally demonstrated at physiologically-relevant Al concentrations (10-100 nm [155,157]) and at levels that have been reported in AD chromatin fractions [185].…”

Section: Effects On Chromatin Structure and Transcriptionmentioning

confidence: 99%

“…increasing the rate of trans-membrane diffusion [163] and selectively changing saturable transport systems [27,68,163,175] Facilitates glutamate transport across the BBB and potentiates glutamate excitotoxicity [50,[133][134][135]137] Decreases antioxidant activity of SOD and catalase in the brain [164] Increases cerebellar levels of nitric oxide synthase (NOS) [232] Augments specific neuro-inflammatory and pro-apoptotic cascades by inducing transcription from a subset of HIF-1 and NF-Bdependent promoters (A␤PP, IL-1␤ precursor, cPLA 2 , COX-2 and DAXX [70,209,237]) Activates microglia, exacerbates inflammation and promotes degeneration of motor neurons [87,273] Nuclear effects Binds to phosphonucleotides and increases the stability of DNA [236] Binds to linker histones, increases chromatin compaction, depresses transcription [65,157,174,[182][183][184][185] Inhibits RNA polymerase activity [155][156][157] Reduces the expression of the key cytoskeletal proteins ␣-tubulin and ␤-actin [155,274] Downregulates the expression of the light chain of the neuron-specific neurofilament (NFL) gene in 86% of surviving neurons in the superior temporal gyrus of AD patients [184] Up-regulates well known AD-related genes: amyloid precursor-like protein (APLP)-1 and APLP-2, tau and A␤PP, in human neuroblastoma cells when complexed with A␤, to a larger extent than other A␤-metal complexes (A␤-Zn, A␤-Cu and A␤-Fe) [14] Up-regulates HIF-1 and NF-B -dependent gene expression (see Metabolic and inflammatory effects)…”

Section: Introductionmentioning

confidence: 99%

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Aluminum and Alzheimer's Disease: After a Century of Controversy, Is there a Plausible Link?

Tomljenovic

2011

JAD

332

197

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The brain is a highly compartmentalized organ exceptionally susceptible to accumulation of metabolic errors. Alzheimer's disease (AD) is the most prevalent neurodegenerative disease of the elderly and is characterized by regional specificity of neural aberrations associated with higher cognitive functions. Aluminum (Al) is the most abundant neurotoxic metal on earth, widely bioavailable to humans and repeatedly shown to accumulate in AD-susceptible neuronal foci. In spite of this, the role of Al in AD has been heavily disputed based on the following claims: 1) bioavailable Al cannot enter the brain in sufficient amounts to cause damage, 2) excess Al is efficiently excreted from the body, and 3) Al accumulation in neurons is a consequence rather than a cause of neuronal loss. Research, however, reveals that: 1) very small amounts of Al are needed to produce neurotoxicity and this criterion is satisfied through dietary Al intake, 2) Al sequesters different transport mechanisms to actively traverse brain barriers, 3) incremental acquisition of small amounts of Al over a lifetime favors its selective accumulation in brain tissues, and 4) since 1911, experimental evidence has repeatedly demonstrated that chronic Al intoxication reproduces neuropathological hallmarks of AD. Misconceptions about Al bioavailability may have misled scientists regarding the significance of Al in the pathogenesis of AD. The hypothesis that Al significantly contributes to AD is built upon very solid experimental evidence and should not be dismissed. Immediate steps should be taken to lessen human exposure to Al, which may be the single most aggravating and avoidable factor related to AD.

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Section: Aluminum Toxicokinetics Across the Brain Barriers: More Thansupporting

confidence: 80%

Section: Aluminum Toxicokinetics Across the Brain Barriers: More Thanmentioning

confidence: 99%

Section: Effects On Chromatin Structure and Transcriptionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Aluminum and Alzheimer's Disease: After a Century of Controversy, Is there a Plausible Link?

Tomljenovic

2011

JAD

332

197

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“…NPXTs derived from cultured HEK cells were subjected to EMSA (42,43). AP1, AP1-like, AP2, Egr1 (zif268), NF-KB, the GAS and SIE elements, and TFIID, and their mutant oligonucleotides containing the relevant consensus sequences (Table 1) were obtained from Santa Cruz Biotechnology or were synthesized at the Louisiana State University Medical Center Core Facility as single-stranded DNAs and then annealed by Table 1.…”

Section: Methodsmentioning

confidence: 99%

Budesonide epimer R or dexamethasone selectively inhibit platelet-activating factor-induced or interleukin 1β-induced DNA binding activity ofcis-acting transcription factors and cyclooxygenase-2 gene expression in human epidermal keratinocytes

Lukiw¹,

Peláez²,

Martínez³

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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To further understand the molecular mechanism of glucocorticoid action on gene expression, DNA-binding activities of the cis-acting transcription factors activator protein 1 (AP1), AP2, Egr1 (zif268), NF-B, the signal transducers and activators of transcription proteins gamma interferon activation site (GAS), Sis-inducible element, and the TATA binding protein transcription factor II D (TFIID) were examined in human epidermal keratinocytes. The cytokine interleukin 1␤ (IL-1␤) and platelet-activating factor (PAF), both potent mediators of inflammation, were used as triggers for gene expression. Budesonide epimer R (BUDeR) and dexamethasone (DEX) were studied as potential antagonists. BUDeR or DEX before IL-1␤-or PAF-mediated gene induction elicited strong inhibition of AP1-, GAS-, and in particular NF-B-DNA binding (P < 0.001, ANOVA). Only small effects were noted on AP2, Egr1 (zif268), and Sis-inducible element-DNA binding (P > 0.05). No significant effect was noted on the basal transcription factor TFIID recognition of TATA-containing core promoter sequences (P > 0.68). To test the hypothesis that changing cis-acting transcription factor binding activity may be involved in inflammatoryresponse related gene transcription, RNA message abundance for human cyclooxygenase (COX)-1 and -2 (E.C.1.14.99.1) was assessed in parallel by using reverse transcription-PCR. Although the COX-1 gene was found to be expressed at constitutively low levels, the TATA-containing COX-2 gene, which contains AP1-like, GAS, and NF-B DNA-binding sites in its immediate promoter, was found to be strongly induced by IL-1␤ or PAF (P < 0.001). BUDeR and DEX both suppressed COX-2 RNA message generation; however, no correlation was associated with TFIID-DNA binding. These results suggest that on stimulation by mediators of inflammation, although the basal transcription machinery remains intact, modulation of cis-activating transcription factor AP1, GAS, and NF-B-DNA binding by the glucocorticoids BUDeR and DEX play important regulatory roles in the extent of specific promoter activation and hence the expression of key genes involved in the inflammatory response.Glucocorticosteroids (GCs) have long been used therapeutically as immunosuppressive and anti-inflammatory agents; however, the mechanism of their activity is only recently becoming understood at the genetic level. GCs interact with an intracellular GC receptor, which subsequently translocates to the nucleus as a ligand-activated transcriptional modulator. In turn, the GC receptor regulates the expression of genes such as those encoding cytokines, matrix metalloproteinases, and cell adhesion molecules known to be critical to both inflammation and the immune response (1, 2). Besides a direct "type 1" interaction with a palindromic GC responsive element in GC-sensitive gene promoters (3, 4), functions of the GC receptor also include a "type 2" interaction with chromatin-associated cis-acting transcription factors. For example, the GC receptor can physically interact with the Fos and J...

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Aluminium and the risk for alzheimer's disease

McLachlan

1995

Environmetrics

186

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SUMMARYThe strength of the evidence implicating aluminium as an important factor in the dementia of Alzheimer's disease (AD) is reviewed. We submit that the weight of the epidemiological and biological arguments is considerable. While a complete understanding has not been achieved, we recommend lowering aluminium exposure in municipal drinking water to below 50 pg/l in at least the province of Ontario. The Ministry of Energy and the Environment of Ontario maintains a drinking water surveillance programme which has provided a database for more than 10 years. This database has permitted assessment of the relative risk for AD using four independent measures of disease prevalence: 1. weighted residential history as a measure of exposure in autopsy-verified AD cases and controls; 2. first admission hospital discharge diagnoses of AD and controls; 3. death certificate rates for AD and presenile dementia; 4. impairments in cognitive function in elderly males. Taken together, many of the criticisms applied to epidemiological studies conducted elsewhere and reaching similar conclusions have been met. A vast experimental database on aluminium neurotoxicity, rapid advances in the understanding of the molecular basis of AD, and comparison studies between human brains exposed to chronic low dose aluminium exposure secondary to renal failure and AD, lend strong biological support to the conclusions reached by the epidemiological studies. The factors initiating AD, how aluminium gains access to the brain in AD, and the relative contributions of food, pharmaceuticals and skin absorption, remain unknown. While a full understanding is not in hand, the devastating nature of the disease, the lack of an effective treatment or prevention and the high cost to the health care system, together with the human costs, weighed against the relative cost of moderately reducing drinking water aluminium concentration to reduce exposure indicate that action is both reasonable and timely. KEY WORDSAlzheimer's disease; aluminium ALZHEIMER'S DISEASE: THE PROBLEMAlzheimer's disease (AD) is a slowly progressive, lethal, brain disorder which affects memory and other cognitive functions. AD is the most common cause of senile dementia and the prevalence in the age group over 65 years has been estimated to range between 9 per cent' and 5-5 per cent.2 The onset of AD is uncommon under the age of 65 (presenile dementia), but no less tragic. About 10 per cent of all cases occur in families (known as familial Alzheimer's disease (FAD)) and are inherited as an autosomal dominant disorder.The AD degenerative process renders victims mentally incompetent with progressive loss of self-help skills. The prolonged clinical course of the disease over ten or more years results in a particularly heavy burden of care upon the next-of-kin, the community social support systems, and, eventially, chronic care institutions, where the terminal phase may last three or more years. The brain changes which distinguish AD from all other causes of senile dementia are loss of neurons...

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Linker histone‐DNA complexes: enhanced stability in the presence of aluminum lactate and implications for Alzheimer's disease

Cited by 25 publications

References 20 publications

Aluminum and Alzheimer's Disease: After a Century of Controversy, Is there a Plausible Link?

Aluminum and Alzheimer's Disease: After a Century of Controversy, Is there a Plausible Link?

Budesonide epimer R or dexamethasone selectively inhibit platelet-activating factor-induced or interleukin 1β-induced DNA binding activity ofcis-acting transcription factors and cyclooxygenase-2 gene expression in human epidermal keratinocytes

Aluminium and the risk for alzheimer's disease

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