L. Teillet, Ph. van den Bosch de Aguilar, G. Hamon, B. Corman, T. Cudennec, F. Puisieux

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Is zinc implicated in the formation of the amyloid deposits characteristic of Alzheimer's disease ?

B. Corman

Zinc is an element whose extracellular concentration is relatively low (below 1 µM). In the brain it may sometimes reach local concentrations above 100 µM in the synaptic cleft during intense neuronal activity. At these concentrations, zinc can induce aggregation of b-amyloid peptides produced by cleavage of APP (ß-amyloid precursor protein). Several experimental arguments suggest that this role of zinc in the aggregation of b-amyloid peptides could play a part in the pathogenesis of Alzheimer's disease. First, metals such as zinc or copper in aqueous solution can complex with b-amyloid peptides. Second, zinc deposits in the brain are larger in patients with Alzheimer's disease, and in particular are localized in those areas presenting amyloid deposits. Third, the administration of a chelator of copper and zinc such as clioquinol to transgenic mice that develop the symptoms of Alzheimer's disease prevents the accumulation of insoluble ß-amyloid peptides in the brain and improves the animals' behavior. Prompted by these findings, a Korean team, together with several American groups, has sought to correlate the accumulation of b-beta-amyloid peptides with zinc deposits in transgenic mouse models. Mice carrying an hAPP+ mutation, which induces b-amyloid deposits in the brain comparable to those seen in Alzheimer's disease, were crossed with mice lacking the gene for zinc transporter 3 (ZnT3), which is present in the synaptic endings. Three lines resulting from this cross were analyzed. Animals devoid of ZnT3 did not differ from control mice in terms of body weight, fertility, longevity or behavior. The microscopic structure of their nerve endings was also identical, although the presence of zinc was no longer detectable by immunofluorescence in the synaptic clefts of the ZnT3-/- mice. From 12 months up to 24 months, the number and size of the amyloid plaques, and the presence of zinc, increased sharply in the synaptic cleft in the hAPP+ mice expressing ZnT3 receptors, whereas at the same age this accumulation was very modest in ZnT3-/- mice. Curiously, the deposits of ß-amyloid peptides and of zinc were greater in the senescent females than in males expressing ZnT3, whereas this difference disappeared in the ZnT3-/- mutants lacking ZnT3. The authors conclude from these results that zinc, bound by its T3 receptor and released into the synaptic cleft, could contribute to the aggregation of b-amyloid peptides and to their deposition in the brain. Apart from therapeutic approaches designed to inhibit the formation from APP of ß-amyloid peptides, or to increase their clearance, there may be a role for the clinical use of chelators to lower local zinc concentrations in the brain, in order to prevent or slow the development of Alzheimer's disease. It is naturally necessary to ensure that this therapeutic approach is applicable to humans and that any positive effects it may have are not counterbalanced by substantial side effects.
Lee JY, Cole TB, Palmiter RD, Won Suh S, Koh JY. Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish APP transgenic mice. Proc. Natl. Acad. Sci. 2002, 99: 7705-7710.

Does regular consumption of tea have a beneficial effect on bone mineral density?

T. Cudennec

Tea contains over 4,000 chemical compounds likely to act on body composition. As with phytoestrogens or fluorides, it has been suggested that numerous compounds found in tea extracts may have a preventive action in cardiovascular diseases, atherosclerosis, cancers, and also bone mineral density (BMD). These hypotheses prompted a Taiwanese group to study in depth the correlation between habitual tea consumption and BMD. The authors enrolled in this epidemiological study 497 men and 540 women, all 30 years and older, who were free of bone disease and were receiving no treatment affecting bone growth. The subjects answered a questionnaire on their tea drinking habit and lifestyle. Dual-energy X-ray absorptiometry was used to measure BMD of the whole body, the first four lumbar vertebrae, and the head of the femur. Three questions were investigated: Is there a relation between tea consumption and BMD? If there is an effect, is it dose-dependent? Which tea consumption characteristics most affect BMD? Almost half of the study participants had on average been regular tea drinkers for approximately ten years. Comparison of occasional and habitual tea drinkers showed that vertebral BMD was higher in the latter. BMD was higher in all the regions measured in those who had been regular tea drinkers for at least a decade. Taking into account the different risk factors conventionally recognized in bone weakening, such as sex, age, body mass index, or total physical activity, tea drinking habit again appeared the most significant in the variations in BMD of the regions examined. Among the various characteristics of tea consumption, the duration of tea consumption was the sole independent determinant for BMD. The authors propose several mechanisms of action. Tea contains fluorides which may limit progression of osteoporosis. Flavonoids, particularly phytoestrogens, may play a role in enhancing BMD. Lastly, in vivo studies in mice have shown that tea extracts have an inhibitory activity on bone resorption and a protective action against clastogenic activity. It seems therefore that the regular consumption of tea over more than ten years has significant beneficial effects on BMD of the whole body, lumbar spine and hip regions in adults.
Chih-Hsing Wu, Yi-Ching Yang, Wei-Jen Yao, Feng-Hwa Lu, Jin-Shang Wu, Chih-Jen Chang. Epidemiological Evidence of Increased Bone Mineral Density in Habitual Tea Drinkers. Arch. Intern. Med. 2002: 162; 1001-1006

A vitamin C-rich diet could reduce the risk of cataract

G. Hamon

Cataract is a frequent cause of visual disorders in the elderly. Few studies have been done in Europe on the risk factors likely to influence cataract development. Some authors have sought to incriminate diet and its antioxidant composition in the development of cataracts, but the published results are contradictory. While experiments in animals have demonstrated a protective role of vitamin C, epidemiological studies have yet to point to such a clear conclusion in humans.A Spanish case-control study in a Mediterranean population was conducted to analyze the putative relations between the risk of cataract and the dietary intake of antioxidant vitamins or minerals like zinc and selenium. The study included 677 subjects 55 to 74 years of age (mean 66), of which 334 were controls devoid of lens opacity on ophthalmological examination. The patients included had uni- or bilateral cataract, of various types. The participants were all from the region of Valencia in Spain. Each of the two groups included the same proportion of men and women. A questionnaire was used to analyze the eating habits and lifestyle of the participants. The circulating concentrations of vitamins C, E and A, and of four carotenoid compounds (b-carotene, a-carotene, b-cryptoxanthin and lycopene) were measured in fasting blood samples.The diet of the study population was particularly rich in vitamin C, with a mean daily intake of 157±77 mg. In this cohort, the subjects with the highest vitamin C intake had a lower risk of cataract, with the most marked beneficial effects being observed above 135 mg/day. This observation was confirmed by the measurement of vitamin C concentrations in the blood which, when above 49 µmol/L, were accompanied by a 64% drop in the risk of cataract. Vitamin E, like selenium, only had a marginal beneficial effect. In contrast, moderately elevated lycopene concentrations (> 0.30 µmol/L) were associated with a 46% increase in risk. A protective effect was noted with vitamin A at blood concentrations between 2.5 and 2.8 µmol/L, but at higher concentrations the risk rose.These data recorded in a population characterized by a diet relatively rich in vitamin C, essentially because of the regular consumption of citrus fruits, strengthens the notion of a protective effect of antioxidants, particularly vitamin C, in the process of aging and lens opacification.
Valero MP, Fletcher AE, De Stavola BL, Vioque J and Alepuz VC. Vitamin C is associated with reduced risk of cataract in a mediterranean population. J. Nutr, 2002, 132: 1299-1306

The protective effect of ischemic preconditioning is preserved in food-restricted senescent rats

F. Puisieux

Preconditioning is a powerful mechanism of endogenous protection against ischemia. One or more episodes of brief ischemia render a tissue more resistant to subsequent prolonged ischemia. Such a protective mechanism has been demonstrated in animals in various tissues such as the heart, brain, liver, small intestine and skeletal muscle. Various studies have shown that the protective effect of preconditioning is lost with age. Consistent with this is the fact that in the elderly there is a reduction in the protective effect of coronary ischemia preceding infarction, or of warm-up prior to exercise, which could be explained by preconditioning. The mechanisms underlying tolerance of ischemia induced by preconditioning are not yet fully elucidated. In the murine model, catecholamines produced by intramyocardial nerve endings may one mediator of tolerance induction. It has been suggested that the age-related loss of the protective effect of preconditioning could be linked to deficient production of noradrenaline in response to ischemic stimuli, since it has been demonstrated that the production of noradrenaline by intracardial nerve endings decreases with age. Physical activity and caloric restriction have recognized "anti-aging" effects. Caloric restriction extends the lifespan of rodents. The authors of this article have already shown in a previous report that prolonged physical training preserves the favorable effect of preconditioning in senescent rats, probably by maintaining an elevated production of noradrenaline in response to ischemic stimuli. In this new study the authors hypothesize that caloric restriction may have the same effect as physical exercise. To verify this hypothesis, they studied the effects of ischemic preconditioning on isolated hearts from young adult rats (6 months) and senescent rats (24 months) some fed ad libitum and others subject to 40% caloric restriction since the age of 12 months. The prolonged ischemia lasted 20 minutes, and in the preconditioning group was preceded by a 2-minute ischemia, the two being separated by an interval of 10 minutes. To study the effect of the release of noradrenaline in this experimental situation, a third group of preconditioned rats was given an intraperitoneal injection of reserpine, which induces peripheral depletion of stocks of catecholamines. Throughout the experiment and up to 40 minutes after the prolonged ischemia, the following hemodynamic parameters were measured: developed pressure DP, telediastolic pressure, the first derivative of the pressure variation dP/dt which reflects contractility and coronary effluent. Noradrenaline was assayed in coronary blood before and after the brief ischemia. After 20 minutes of ischemia, the DP and dP/dt dropped and the telediastolic pressure rose markedly in all groups. Telediastolic pressure increased less in unconditioned young rats than in unconditioned senescent rats, but more in preconditioned young rats. The most significant differences were observed during the 40-minute reperfusion which followed the prolonged ischemia. During this phase, the hemodynamic parameters improved progressively in all the groups, but very unequally. In the unconditioned groups, the improvement was faster and more complete in young rats than in senescent rats. It was also better in food-restricted senescent rats than in senescent rats fed ad libitum. The preconditioning accelerated the hemodynamic recovery and reduced the incidence of late ventricular fibrillation in young adult rats and in food-restricted senescent rats. There was no significant effect, however, in senescent ad libitum-fed rats. Before preconditioning, noradrenaline levels in the coronary blood flow were similar in the three preconditioned groups, but after brief ischemia they increased more in young rats than in food-restricted senescent rats fed ad libitum. Lastly, pretreatment with reserpine blocked release of noradrenaline after brief ischemia and abolished the favorable effects of preconditioning on the recovery of hemodynamic parameters and on arrhythmia, in both young rats and food-restricted senescent rats. Preconditioning therefore improves the hemodynamic and electrical parameters after prolonged ischemia in young adult rats and food-restricted senescent rats, but has no effect on senescent rats fed ad libitum. Caloric restriction thus allows the preservation with age of the protective effect of ischemic preconditioning, which may be explained by the maintenance of the noradrenergic response to the preconditioning stimulus. The excess mortality of elderly subjects suffering coronary ischemic events cannot be fully explained by comorbidity. It is possible that the loss of preconditioning-induced protection may also contribute. In theory, a reduction in body mass index achieved by food restriction could restore the protective effect of ischemic preconditioning in elderly subjects.
Abete P, Testa G, Ferrara N, De Santis D, Capaccio P, Viati L, Calabrese C, Cacciatore F, Longobardi G, Condorelli M, Napoli C, Rengo F. Cardioprotective effect of ischemic preconditioning is preserved in food-restricted senescent rats. Am J Physiol Heart Circ Physiol 2002; 282: H1978-H1987

What is the relation between plasma homocysteine and hospitalizations for cardiovascular disease?

L. Teillet

It is now readily admitted that high plasma homocysteine is associated with the occurrence of cardiovascular disease. For several years, it has also been considered that plasma homocysteine is an independent side factor of arterial obstruction and venous thrombosis, which is proportional to concentration. Yet although many prospective and retrospective studies involving over 20,000 subjects point in this direction, other studies have not shown such an association. It is also known that high plasma homocysteine may be linked to deficiency in vitamin B12 or in folates, or to renal insufficiency. In the same way, elevated plasma homocysteine appears more frequent with age in both men and postmenopausal women and seems to be associated with certain behavioral characteristics such as smoking, high coffee intake, and sedentary life. A more tenuous association has also been reported with other cardiovascular risk factors, such as blood pressure and plasma cholesterol. These various putative risks and associations were investigated by a Norwegian team of epidemiologists and university research scientists in the region of Bergen, in the Hordaland Homocysteine Study, which studied the link between cardiovascular disease and plasma homocysteine. This team examined the potential association between plasma total homocysteine, which comprises free and protein-bound fractions, and hospitalization prompted either by a cardiovascular disease or by coronary revascularization surgery. The analysis related to data initially from 17,361 subjects in the age ranges 40 to 42 years and 65 to 67 years. On inclusion in the study, between 1992 and 1993, a certain number of pertinent parameters were recorded, such as weight, height, blood pressure, plasma lipids and plasma homocysteine. The existence of risk factors or a history of cardiovascular disease were also noted. The diagnoses on discharge from hospital and the causes of death were analyzed until the end of the study in May 1998. On inclusion in the study, the subjects who already had a cardiovascular disease were those with the highest plasma homocysteine. The risk of hospitalization due to a cardiovascular event increased significantly with plasma homocysteine, but only in the group of older subjects, among whom hospitalization increased in frequency as plasma homocysteine rose. This link between elevated plasma homocysteine and hospitalization was strengthened where there was a history of cardiovascular disease. In the light of these results, the authors of this epidemiological study concluded that in older patients elevated plasma homocysteine is a good predictor of hospitalization for cardiovascular disease, especially when there is a clear cardiovascular history. These results also support the hypothesis that homocysteine interacts with classical risk factors to facilitate or precipitate the occurrence of an acute cardiovascular event.
Nurk E, Tell GS, Vollset SE, Nygard O, Refsum H, Ueland PM. Plasma total homocysteine and hospitalizations for cardiovascular disease : the Hordaland Homocysteine Study. Arch Intern Med 2002;162:1374-1381.

A link between amyloid deposits and learning deficits: a study in transgenic mice

Ph. van den Bosch de Aguilar

The mechanisms underlying brain deficits manifested in Alzheimer's disease remain enigmatic. One widely identified risk factor is age. Another is genetic in nature and is present in the familial form of the disease through transmission of specific genes that have undergone a mutation leading to overproduction of b-amyloid peptide and hence to an increase in the number of senile plaques. As the level of b-amyloid is also higher in the non-familial form, one may suspect that the regulation of b-amyloid production is a key factor in the pathogenesis of Alzheimer's disease, whether familial or not. Regulation of beta--amyloid production is a complex process. Beta-amyloid is derived from a membrane amyloid precursor protein (APP) cleaved by proteolytic enzymes, the a-, b- and g-secretases. b-Secretase is a membrane-bound aspartyl protease. a-Secretase is a metalloprotease. g-Secretase is an oligomeric complex which comprises presenilins, the catalytic moiety of this protease. The activity of these different enzymes leads to the deposition of insoluble peptides comprising either 40 or 42 amino acids, the latter being highly hydrophobic and the main constituent of senile plaques. The respective roles of these different enzymes in the growth of senile plaques and the resulting effects on brain function are poorly understood. With this in mind, the authors studied three lines of transgenic mice carrying human mutations: the first carries a presenilin mutation, the second an APP mutation, and the third both mutations. The mice were tested at various time points, using histopathological, biochemical and behavioral methods. Senile plaques developed faster in the animals carrying both mutations, since they appeared at the age of seven months and increased in number, leading to invasion of various brain regions by nine months. Plaques appeared sporadically in the APP mutant animals at nine months, while in the presenilin mutants they were detected at 24 months only. Behavioral disorders, particularly learning deficits, were identified in the mice bearing both mutations as early as five months of age, before the plaques were histopathologically identifiable. The learning disorders are known to be specific to the hippocampus, the nexus of memorization processes and spatial orientation in mice. Overproduction of beta-amyloid peptide leads to overstimulation of a-nicotinic acetylcholine receptors which then continuously activate the protein kinase cascade. This uncontrolled stimulation, which undermines the efficiency of the hippocampus, causes the behavioral disorders. This study in mice thus establishes a link between the genetic mechanisms responsible for the amyloid deposits and the resulting brain disorders in Alzheimer's disease.
K.T. Dineley; X. Xia, D. Buy, J.D. Sweatt and H. Zheng__ Accelerated plaque accumulation, associative learning deficits, and up-regulation of a7 nicotinic receptor protein in transgenic mice co-expressing mutant human preseniline 1 and amyloid precursor. J. Biol. Chem. 2002, 277 : 22768-22780