Olivier Guillard

Mechanism of Alzheimer's disease : arguments for a neurotransmitter-aluminium complex implication

The authors are convinced that in Alzheimers disease, as in Downs syndrome and Guam-Parkinson dementia, one may find an alteration in blood brain barrier transfer and a resultant imbalance in mineral metabolism. Metals, such as aluminium, which in vivo yield stable complexes with aspartic and glutamic acids act as previously been clearly shown with glutamic acid; they cross the blood brain barrier, and are deposited in the brain. The authors explain how amyloid protein or neurofibrillary tangles could well be produced by aluminium complex formation. Whithin the brain, in the form precisely of aluminium complex,l-glutamic acid is consequently unable to detoxify ammonia from neurons and to produce L-glutamin. Accumulation of ammonia is subsequently responsible for the neuronal death, affecting each and every neurotransmitter system.

Group I metabotropic glutamate receptors activate the p70S6 kinase via both mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase (ERK 1/2) signaling pathways in rat striatal and hippocampal synaptoneurosomes

Group I metabotropic glutamate receptors (mGluRs) have been demonstrated to play a role in synaptic plasticity via a rapamycin-sensitive mRNA translation signaling pathway. Various growth factors can stimulate this pathway, leading to the phosphorylation and activation of mammalian target of rapamycin (mTOR), a serine/threonine protein kinase that modulates the activity of several translation regulatory factors, such as p70S6 kinase. However, little is known about the cellular and molecular mechanisms that bring the plastic changes of synaptic transmission after stimulation of group I mGluRs. Here, we investigated the role of the mTOR-p70S6K and the ERK1/2-p70S6K pathways in rat striatal and hippocampal synaptoneurosomes after group I mGluR stimulation. Our findings show that (S)-3,5-dihydroxyphenylglycine (DHPG) increases significantly the activation of mTOR and p70S6K (Thr389, controlled by mTOR) in both brain areas. The mTOR activation is dose-dependent and requires the stimulation of mGluR1 subtype receptors as for the p70S6K activation observed in striatum and hippocampus. In addition, the p70S6K (Thr421/Ser424) activation via the ERK1/2 activation is increased and involved also mGluR1 receptors. These results demonstrate that group I mGluRs are coupled to mTOR-p70S6K and ERK1/2-p70S6K pathways in striatal and hippocampal synaptoneurosomes. The translational factor p70S6K could be involved in the group I mGluRs-modulated synaptic efficacy.

Chronic administration of aluminium l-glutamate in young mature rats: effects on iron levels and lipid peroxidation in selected brain areas

Clinical and experimental studies have demonstrated the neurotoxicity of aluminium (Al), notably as a result of lipid peroxidation in vitro. We previously showed that Al is able to cross the blood-brain barrier as an L-glutamate complex and be deposited in rat brain. The present work in young mature rats investigated the in vivo effects of chronic Al-L-glutamate treatment on Al and iron movement in plasma and selected brain regions. Brain lipid peroxidation was determined by evaluating the production of thiobarbituric acid reactive substances (TBARS) and analysing polyunsaturated fatty acids (PUFAs) such as C20:4n-6 and C22:6n-3. Our results indicate that iron concentration was decreased in plasma and that Al accumulated especially in striatum where iron levels were decreased and in the hippocampus where TBARS were increased without PUFA modifications. These data show that Al administered chronically as an L-glutamate complex is neurotoxic in vivo and thus provides a good model for studying Al toxic mechanisms.

Aluminum transfer as glutamate complex through blood-brain barrier: possible implication in dialysis encephalopathy.

In vitro distribution of aluminium between plasma and erythrocytes has been studied in the presence of variable amounts of sodiuml-glutamate. With a red blood cell suspension in isotonic sodium chloride, aluminium remains confined in erythrocytes even when the sodiuml-glutamate concentration increases in the medium.Aluminium initially present in plasma penetrates red blood cells when sodiuml-glutamate increases in whole blood, showing that this metal is able in vitro to cross the erythrocyte membrane as glutamate complex. In vivo experiments with male Wistar rats prove that aluminium is also able to pass the blood-brain barrier as glutamate complex and deposit in the brain cortex.

Modification of the blood-brain barrier through chronic intoxication by aluminum glutamate: Possible role in the etiology of Alzheimer’s disease

The authors have used an experimental rat model of chronic aluminum (Al) intoxication to reproduce pathological signs analogous to those observed in humans for Alzheimer’s disease or dialysis encephalopathy. Preliminary chronic intoxication was achieved during 5 wk by daily subcutaneous injection of a suspension of glutamate and Al prior to intravenous (iv) administration of sodiuml-glutamate and Al chloride. A significant increase in Al content was observed in different areas of the brain, such as the hippocampus, the occipito-parietal cortex, the cerebellum, and the striatum. Moreover, half of the animals subcutaneously treated with Al glutamate had neurological disturbances; such as trembling, equilibrium difficulties, and convulsions leading to death about 1 h after iv administration. A significant increase in glutamic acid at the level of the occipito-parietal cortex was found in comparison with controls, which received only sodiuml-glutamate or saline solution. These results show that the Al-l-glutamate complex may well induce a modification of the blood-brain barrier.

Determination of lead in whole blood: comparison of the LeadCare blood lead testing system with Zeeman longitudinal electrothermal atomic absorption spectrometry.

This study compares the efficiency of blood lead level analysis by graphite furnace atomic absorption spectrometry (GFAAS) and the portable LeadCare Blood Lead Testing System (LCS). Recoveries of two added lead concentrations of 22 and 42 micrograms/dL ranged from 102.4 to 105.5% for LCS and from 96.3 to 97.2% for GFAAS. Measurement of a certified sample (Certified Danish Whole Blood) at a blood lead concentration of 26.2 micrograms/dL gave within- and between-run coefficients of variation which were both approximately 8% by LCS and 2% by GFAAS. Comparison of the tested method (LCS) versus GFAAS from analysis of 76 samples of blood lead collected from workers in different industrial sectors showed imperfect overall correlation (r = 0.95). The LCS is quite suitable for screening purposes, but requires the use of non-frozen blood collected less than 24 h before. Conservative threshold values should be applied when using the LCS for initial screening in the field.

Role of aluminium in skin reactions after diphtheria-tetanus-pertussis-poliomyelitis vaccination: An experimental study in rabbits

The occurrence of subcutaneous nodules at the injection site is one of the complications of diphtheria-tetanus-pertussis-poliomyelitis vaccination, but the causes and mechanisms involved are still poorly understood. An experimental study in the New Zealand rabbit enabled us to determine the frequency of occurrence of these nodules, how long they persist and the histopathologic features of the cells involved. Aluminium (Al) assays by electrothermal atomic absorption spectrometry allowed us to study concentrations both in nodules and the organism (serum, normal skin). The results show an absence of Al diffusion outside nodules, a correlation between infiltrate intensity and Al concentration in nodules and modifications in the histological constituents of nodule cells. The histological picture indicates a foreign body reaction to Al. All these data underscore the role of Al in the formation of early postvaccinal nodules at the injection site.

Pharmacological inhibition of PKR in APPswePS1dE9 mice transiently prevents inflammation at 12 months of age but increases Aβ42 levels in the late stages of the Alzheimer's disease.

The double-stranded RNA-dependent protein kinase (PKR) is switched on by a wide range of stimuli, including the amyloid peptide. Then, PKR transmits signals to the translational machinery, apoptosis and inflammatory signaling pathways by interacting with some adapters. In virus-infected cells, PKR engages the nucleus factor κB (NF-κB) pathway. In many models of Alzheimers disease (AD) and patients with AD, PKR was activated. Furthermore, there is strong evidence implicating the inflammatory process in the AD brain. However, the PKR involvement in inflammatory responses in AD is not elucidated. Based on our previous in vitro results, the aim of this study was to evaluate the effects of a pharmacological inhibition of PKR in inflammation in APPswePS1dE9 transgenic mice. Our results showed that PKR inhibition prevented the NF-κB activation and production of tumor necrosis factor alpha (TNFα) and interleukin (IL)-1β at 12 months of age without decrease of Aβ42 levels and memory deficits. Surprisingly, PKR inhibition failed to prevent IL-1β- mediated inflammation and induced a great increase in β-amyloid peptide (Aβ42) levels at 18 months of age. In this model, our findings highlight the lack of relationship between inflammation and Aβ42 levels. Moreover, the age-dependent inflammatory response must be carefully taken into account in the establishment of an anti-inflammatory therapy in AD.

Copper-induced lipid peroxidation and hemolysis in whole blood: evidence for a lack of correlation

In order to establish a possible relationship between hemolytic and peroxidant activities of copper ions, lipid peroxidation was studied in plasma and whole blood incubated for 24 h with different concentrations of copper. The lipid peroxidation was investigated by the determination of thiobarbituric acid-reactive species, conjugated dienes and fluorescent lipid chromophores. The copper-induced lipoperoxidation was clearly demonstrated in plasma incubated with high concentrations of copper (12.10(-4) and 20.10(-4) M); in whole blood, all the lipoperoxidation products were increased in the plasma, while the fluorescent lipid chromophores remained unchanged in red cells. With a copper concentration similar to that found in acute copper intoxication (4.10(-4) M) no lipoperoxidation was observed and yet hemolysis occurred, reduced glutathione (GSH) decreased dramatically and methemoglobin (MetHb) increased. From these results, we assume that, despite its prooxidant activity and its capacity to produce lipoperoxidation, it has not been proven that copper ions at pathophysiological concentrations induce hemolysis by an oxidative mechanism.

If exposure to aluminium in antiperspirants presents health risks, its content should be reduced

Since aluminium (Al) pervades our environment, the scientific community has for many years raised concerns regarding its safety in humans. Al is present in numerous cosmetics such as antiperspirants, lipsticks and sunscreens. Al chlorohydrate is the active antiperspirant agent in underarm cosmetics and may constitute for Al a key exposure route to the human body and a potential source of damage. An in vitro study has demonstrated that Al from antiperspirant can be absorbed through viable human stripped skin. The potential toxicity of Al has been clearly shown and recent works convincingly argue that Al could be involved in cancerogenic processes. Nowadays, for example, Al is suspected of being involved in breast cancer. Recent work in cells in culture has lent credence to the hypothesis that this metal could accumulate in the mammary gland and selectively interfere with the biological properties of breast epithelial cells, thereby promoting a cascade of alterations reminiscent of the early phases of malignant transformation. In addition, several studies suggest that the presence of Al in human breast could influence metastatic process. As a consequence, given that the toxicity of Al has been widely recognized and that it is not a physiological component in human tissues, reducing the concentration of this metal in antiperspirants is a matter of urgency.