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It's all in the RAGE
138
Notes
mice), both of which are prone to develop atherosclerosis. In transgenic C57BL/6 mice on an atherogenic diet, serum cholesterol levels of high density lipoprotein (HDL), the protective lipoprotein fraction, increased moderately by 35% whereas the levels of apoA-I, the major protein component of HDL, decreased by 23%. These data suggest that apoA-IV can substitute apoA-I and form HDL-like particles. Expression of human apoA-IV in apoE-deficient mice on a normal diet resuited in increased levels of atherogenic lipoprotein fractions, the low and very low density lipoproteins (2fold higher than that in apoE-deficient control mice) whereas no effect on HDL-cholesterol levels was observed. However, transgenic mice of both backgrounds showed a dramatic reduction in the size of atherosclerotic lesions relative to their control mice. Thus, apoA-IV appears to protect against atherosclerosis by a new mechanism that does not involve an increase in apoA-I and HDL-cholesterol levels which were assumed to be the major protective agents until now. In addition, protective effect of apoA-IV appears more efficient than that mediated by apoA-I. Overall, these results suggest possible new avenues for the treatment of atherosclerosis. N Duverger (3) Rhone-Poulenc Rorer, Gencell, 94403 Vitry-Sur-Seine cedex, France
(3) Science 1996;273:966-8
It's all in the R A G E Neurotoxicity due to amyloid-beta peptide (Ab) in Alzheimer's disease can be due to several mechanisms, one of the most frequently suggested being cellular damage consequent to physical contact of neurons with amyloid fibrils. In a recent paper in Nature, Yan and colleagues, at the College of Physicians and Surgeons of Columbia University, identified a quite different mechanism for A b c e l l u l a r interactions: a receptor present on neurons and microglia which selectively engages Ab and promotes induction of cellular stress, especially by oxidant-mediated mechanisms. This cell surface Ab docking site turns out to be identical to the receptor for advanced glycation endproducts (RAGE), a member of the immunoglobulin superfamily which also binds proteins modified by nonenzymatic glycation (the advanced glycation endproducts) and was originally isolated by the same laboratory at Columbia University. While the authors speculate it is unlikely for
R A G E to be a cause of Alzheimer's disease, they consider it to be an excellent candidate as a progression factor which enhances Ab-cellular interactions eventuating in cytotoxicity. Thus, RAGE is a potential therapeutic target in Alzheimer's disease: inhibition of Ab-RAGE binding might diminish At>induced neuronal dysfunction. Since Ab is a complex peptide which forms a range of aggregated structures, it is not unexpected that other cellular Ab binding proteins have been/will be found. However, the presence of RAGE on the surface of neurons, as well as microglia, and the enhanced expression of RAGE observed in Alzheimer's disease, underscores its potential to contribute to the pathologic picture. SD Yah (4) College of Physicians & Surgeons of Columbia University New York, NY 10032, USA (4) Nature 1996;382:685
A new stress-related syndrome of short stature children The study, which was reported in last month's Lancet, describes 29 very short children, boys and girls aged 3 to 13, who were referred to hospital because of their impaired growth. Blood tests showed that the children had lower than normal levels of growth hormone, a protein secreted by the pituitary gland that stimulates growth. Low levels of growth hormone alone can cause short stature but these children had other problems as well. They overate compulsively, a condition called hyperphagia, gorging when food was available and stealing food when it was not. They also hoarded food, got up at night to search for food and even foraged in dustbins. In addition the children drank so much that preventive measures had to be taken at home and at school. All the children came from families in which there was considerable stress and many had been subjected to emotional, physical and sexual abuse. In the hospital the children's contact with their families was limited and they soon began to improve. The hyperphagic appetite disturbance did not persist in any child more than a few days into the admission, according to the researchers. In a few weeks their growth hormone levels began to return to normal. The researchers conclude that they have identified a new syndrome which they call call hyperphagic short stature. They estimate that 3% of short normal children have the syndrome. The syndrome seems to be revers-
Notes
mice), both of which are prone to develop atherosclerosis. In transgenic C57BL/6 mice on an atherogenic diet, serum cholesterol levels of high density lipoprotein (HDL), the protective lipoprotein fraction, increased moderately by 35% whereas the levels of apoA-I, the major protein component of HDL, decreased by 23%. These data suggest that apoA-IV can substitute apoA-I and form HDL-like particles. Expression of human apoA-IV in apoE-deficient mice on a normal diet resuited in increased levels of atherogenic lipoprotein fractions, the low and very low density lipoproteins (2fold higher than that in apoE-deficient control mice) whereas no effect on HDL-cholesterol levels was observed. However, transgenic mice of both backgrounds showed a dramatic reduction in the size of atherosclerotic lesions relative to their control mice. Thus, apoA-IV appears to protect against atherosclerosis by a new mechanism that does not involve an increase in apoA-I and HDL-cholesterol levels which were assumed to be the major protective agents until now. In addition, protective effect of apoA-IV appears more efficient than that mediated by apoA-I. Overall, these results suggest possible new avenues for the treatment of atherosclerosis. N Duverger (3) Rhone-Poulenc Rorer, Gencell, 94403 Vitry-Sur-Seine cedex, France
(3) Science 1996;273:966-8
It's all in the R A G E Neurotoxicity due to amyloid-beta peptide (Ab) in Alzheimer's disease can be due to several mechanisms, one of the most frequently suggested being cellular damage consequent to physical contact of neurons with amyloid fibrils. In a recent paper in Nature, Yan and colleagues, at the College of Physicians and Surgeons of Columbia University, identified a quite different mechanism for A b c e l l u l a r interactions: a receptor present on neurons and microglia which selectively engages Ab and promotes induction of cellular stress, especially by oxidant-mediated mechanisms. This cell surface Ab docking site turns out to be identical to the receptor for advanced glycation endproducts (RAGE), a member of the immunoglobulin superfamily which also binds proteins modified by nonenzymatic glycation (the advanced glycation endproducts) and was originally isolated by the same laboratory at Columbia University. While the authors speculate it is unlikely for
R A G E to be a cause of Alzheimer's disease, they consider it to be an excellent candidate as a progression factor which enhances Ab-cellular interactions eventuating in cytotoxicity. Thus, RAGE is a potential therapeutic target in Alzheimer's disease: inhibition of Ab-RAGE binding might diminish At>induced neuronal dysfunction. Since Ab is a complex peptide which forms a range of aggregated structures, it is not unexpected that other cellular Ab binding proteins have been/will be found. However, the presence of RAGE on the surface of neurons, as well as microglia, and the enhanced expression of RAGE observed in Alzheimer's disease, underscores its potential to contribute to the pathologic picture. SD Yah (4) College of Physicians & Surgeons of Columbia University New York, NY 10032, USA (4) Nature 1996;382:685
A new stress-related syndrome of short stature children The study, which was reported in last month's Lancet, describes 29 very short children, boys and girls aged 3 to 13, who were referred to hospital because of their impaired growth. Blood tests showed that the children had lower than normal levels of growth hormone, a protein secreted by the pituitary gland that stimulates growth. Low levels of growth hormone alone can cause short stature but these children had other problems as well. They overate compulsively, a condition called hyperphagia, gorging when food was available and stealing food when it was not. They also hoarded food, got up at night to search for food and even foraged in dustbins. In addition the children drank so much that preventive measures had to be taken at home and at school. All the children came from families in which there was considerable stress and many had been subjected to emotional, physical and sexual abuse. In the hospital the children's contact with their families was limited and they soon began to improve. The hyperphagic appetite disturbance did not persist in any child more than a few days into the admission, according to the researchers. In a few weeks their growth hormone levels began to return to normal. The researchers conclude that they have identified a new syndrome which they call call hyperphagic short stature. They estimate that 3% of short normal children have the syndrome. The syndrome seems to be revers-