HIGH LIPOPROTEIN(a) LEVEL DOUBLES RISK OF EARLY HEART DISEASEJAMA Press Release
Risk similar to high total cholesterol
CHICAGO--A test not typically included as part of a regular cholesterol screening can be a valuable tool for identifying men at risk of developing premature coronary heart disease (CHD), according to an article in this week's issue of The Journal of the American Medical Association (JAMA).
Andrew G. Bostom, M.D., M.S., of the Framingham Study, Framingham, Mass., and colleagues used data from the Framingham heart study to determine whether elevated lipoprotein(a) [Lp(a)] is an independent risk factor for CHD. The Framingham heart study is a program where the participants' health is tracked for life. "Our findings provide the first prospective evidence that elevated plasma Lp(a) level, determined at a baseline examination, is an independent risk factor for the subsequent development of premature CHD in such individuals," the authors write.
A group of men in the Framingham study between the ages of 20 and 54 were tested and identified to be free of cardiovascular disease between 1971 and 1975. Approximately 15 years later, they were tested again. The researchers discovered that those with an elevated level of Lp(a) in the blood measured semiquantitatively using dectrophoresis during initial testing were almost twice as likely to develop premature CHD (before age 55) as men without elevated levels.
As a predictor of early CHD, elevated Lp(a) was comparable in magnitude to a total cholesterol level of 240 milligrams per deciliter (mg/dL) or more or a high density lipoprotein (HDL) level of less than 35 mg/dL. However, testing for Lp(a) is not commonly performed as part of routine screening for high cholesterol and potential heart disease. There is no established treatment for elevated Lp(a). The authors say the next step in verifying the value of Lp(a) as an indicator of early heart disease is to begin clinical trials to determine if lowering Lp(a) concentrations in potentially high-risk individuals can reduce their risk of developing CHD.
Elevated Plasma Lipoprotein(a) and Coronary Heart Disease in Men Aged 55 Years and YoungerJAMA. 1996;276:544-548 JAMA Abstracts - August 21, 1996
Andrew G. Bostom, MD, MS; L. Adrienne Cupples, PhD; Jennifer L. Jenner, MS; Jose M. Ordovas, PhD; Leo J. Seman, MD, PhD; Peter W. F.Wilson, MD; Ernst J. Schaefer, MD; William P. Castelli, MD
Objective.--To establish whether elevated lipoprotein(a) [Lp(a)], detected as a sinking pre-beta-lipoprotein band on electrophoresis of fresh plasma, is an independent risk factor for the development of premature coronary heart disease (CHD) in men.
Participants.--A total of 2191 men aged 20 to 54 years old who were free of cardiovascular disease when they were examined between 1971 and 1975.
Results.--After a median follow-up of 15.4 years, there were 129 CHD events. The relative risk (RR) estimates (with 95% confidence intervals [CIs]) for premature CHD derived from a proportional hazards model that included age, body mass index, and the dichotomized risk factor covariables elevated plasma Lp(a) level, total cholesterol level of 6.2 mmol/L (240 mg/dL) or more, high-density lipoprotein (HDL) level less than 0.9 mmol/L (35 mg/dL), smoking, glucose intolerance, and hypertension were as follows: elevated Lp(a) level, RR, 1.9 (95% CI, 1.2-2.9), prevalence, 11.3%; total cholesterol level of 6.2 mmol/L or more, RR, 1.8 (95% CI, 1.2-2.7), prevalence, 14.3%; HDL level of less than 0.9 mmol/L, RR, 1.8 (95% CI, 1.2-2.6), prevalence, 19.2%; smoking, RR, 3.6 (95% CI, 2.2-5.5), prevalence, 46.7%; glucose intolerance, RR, 2.7 (95% CI, 1.4-5.3), prevalence, 2.6%; hypertension, RR, 1.2 (95% CI, 0.8-1.8), prevalence, 26.3%. Conclusions.--Elevated plasma Lp(a) is an independent risk factor for the development of premature CHD in men, comparable in magnitude and prevalence (ie, attributable risk) to a total cholesterol level of 6.2 mmol/L (240 mg/dL) or more, or an HDL level less than 0.9 mmol/L (35 mg/dL).
Nando.net ... Reuter Information Service LONDON (Aug 22, 1996) - Two studies published on Wednesday offered hope for a drug that could be used to treat Alzheimer's disease, the most common form of dementia whose sufferers include former U.S. President Ronald Reagan. Both studies suggested ways to close off reactions between brain cells and chemicals or proteins. Many drugs block receptors that allow chemicals or cells to attach to other cells, just as a door could be nailed shut.
New research offers hope for Alzheimer's drug treatment
In Alzheimer's, which affects 15 percent of people over the age of 65 and about half those over 85, proteins gum up and form "plaques" in the brain. The main component of this plaque is amyloid-beta peptide, which is known to be toxic to nerve cells and activates immune cells in the brain.
To have an effect on cells, the peptide would first have to attach. Shi Du Yan of Columbia University in New York and a team of international collaborators looked for the receptor, a kind of door into the cell, where this might happen. They found that a known receptor, the receptor for advanced glycation end products (RAGE), was the door letting the peptide hook up to brain cells. When the peptide interacted with a RAGE, immune system scavenger cells known as microglia were activated -- indicating that brain cells were stressed, they wrote in a report published in the science journal Nature. Microglia are meant to clean up dead or damaged brain cells, and other studies show they may be involved in the brain damage seen in Alzheimer's.
Yan's group said the receptor may help keep the brain clear of the damaging peptides, but may become overwhelmed by the huge amounts produced during Alzheimer's.
In a second study published in Nature, Joseph el Khoury and colleagues, also at Columbia University, found a second interaction involved in Alzheimer's. They found the microglia attach to the peptides via a receptor known as class-A scavenging receptor. They suggest the microglia are trying to clear out the peptide, but get mired down in the plaque. The distressed microglia secrete poisonous chemicals, damaging cells around them. Khoury's group said chemicals that would block this interaction could help delay the onset of Alzheimer's or cause it to progress more slowly.
Receptors for Alzheimer'sS D Yan, X Chen, J Fu, M Chen, H Zhu, A Roher, T Slattery, L Zhao, M Nagashima, J Morser, A Migheli, P Nawroth, D Stern & A M Schmidt
RAGE and amyloid-beta peptide neurotoxicity in Alzheimer's disease
22 August 1996 Nature 382, 685-691 (1996) ... [Below is all that is online -- webmaster]
The 'senile plaques' found in the brain tissue of patients with Alzheimer's disease are aggregates of beta-amyloid peptide (Abeta) infiltrated by microglia and astrocytes. Abeta is known to be neurotoxic, inducing oxidant stress and activating microglia. These effects are thought to be mediated through a cell-surface receptor, and Yan et al. now show that the Receptor for Advanced Glycation End products, or RAGE, is a strong candidate for this role. Not only is oxidative stress induced when Abeta binds to RAGE, but the receptor is abundant on microglia and induces their activation. But RAGE may not be the only receptor involved. In a separate report, El Khoury et al. show that the class A scavenging receptor of microglia can also mediate their adhesion to and activation by Abeta.
Nature 382, 716-719 (1996)
Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils
J El Khoury, S E Hickman, C A Thomas, L Cao, S C Silverstein & J D Loike
Alzheimer's disease is thought to be caused by amyloid-beta, but the details of the degeneration mechanism have so far been missing. Two receptors, called RAGE and SR, now appear to be involved. Though the two seem to be completely unrelated, both are potential drug targets.
Mark P. Mattson and Russell E. Rydel Amyloid ox-tox transducers Nature 382, 674-675 (1996)
San Francisco Examiner
New treatment for Parkinson's disease
SAN FRANCISCO (Aug 23, 1996 2:23 p.m. EDT) -- Doctors at Parkinson's disease clinics around the nation last week began injecting into the brains of patients a protein that specialists say has the potential of dramatically slowing or even reversing the brain disorder.
It may be several years before the value, if any, of the growth factor protein, called GDNF, is known. However, specialists in Parkinson's disease said the product, patented by the California biotechnology company Amgen Inc., looks like an important find in research into the incurable degenerative movement disorder.
"I believe that, eventually, treatment with growth factors or neurotrophic factors (such as GDNF) is going to revolutionize the treatment of disorders like Parkinson's," said Dr. Michael Aminoff, a UC-San Francisco professor of neurology who heads a Parkinson's clinic declared a center of excellence by the National Parkinson's Foundation.
Stock analysts, like scientists, want to see the results of the study before they pass final judgment on Amgen's discovery. David Crossen of Montgomery Securities in San Francisco visited the company's facilities last week and came away persuaded "GDNF is a very important project." Still, he has a hold on the stock until more is known about GDNF's effectiveness.
Amgen, a biotechnology company based in Thousand Oaks, Calif., said it has begun human clinical trials of its product at multiple clinics it would not identify, lest they be overwhelmed by Parkinson's patients seeking help. "I have the necessary desperation," Joan Samuelson of Santa Rosa, Calif., said of her hopes that GDNF or another therapy could cure the disease she has had for 10 years. Samuelson heads Parkinson's Action Network, a national advocacy group.
The experiment, following recent federal approval, will test GDNF's safety in people with moderate to severe Parkinson's. This phase may take a year. More lengthy tests would follow if it is found to be safe. Parkinson's, affecting a million or more Americans, causes muscle tremor, stiffness and weakness. Its symptoms are trembling, a rigid posture, slow movements and a shuffling, unbalanced walk. As many as one-third of Parkinson's patients develop dementia.
The disorder was defined by James Parkinson, a British surgeon. Its victims suffer damage to nerve cell clusters in the brain called the basal ganglia, where a nerve transmitter known as dopamine is made.
The most effective drug used for Parkinson's has been Levadopa, or L-dopa, which the body converts into dopamine, but over the years it loses its effect and may even be toxic. Scientists are at odds over this claim, but they agree L-dopa cannot halt the degeneration of brain cells. Patients typically survive 10 to 15 years after symptoms appear. Many become so rigid that they die in accidents, such as in falls in which hips are broken, said Dr. Jeff Bronstein, a neurologist who heads the UCLA Medical Center Movement Disorder Center. He called Amgen's research "really spectacular."
The research on humans followed successful results with monkeys. In 1982, Michael Carrillo, a drug addict, arrived at Santa Clara Valley Medical Center in Campbell, Calif., nearly paralyzed and unable to speak. Soon, other addicts -- who came to be known as "the frozen addicts" -- came for treatment, all with Parkinson's-like symptoms. They were seen by neurologist Dr. William Langston, who found they had all taken synthetic heroin that had a byproduct called MPTP, which an enzyme in the body converts to a poison. In further study, he found the MPTP attacked the brain cells that produce Parkinson's symptoms when they fail.
Since then, researchers have given monkeys MPTP to produce symptoms similar to those of Parkinson's. The Amgen researchers say they were able to protect dopamine neurons from toxic damage, restore functional activity to dormant dopamine neurons in monkeys and reverse the symptoms of Parkinson's. It remains to be seen if they can do the same in people. "This safety trial gets us to first base, but this a five-or-more-year program," said Amgen spokesman David Kaye. "This is a tragic disease, and we do not want to contribute to expectations getting wildly out of hand."
Crossen, the Montgomery Securities analyst, said he learned that 50 patients are in the trial and that GDNF theoretically corrects rigidity, not the symptomatic tremors.
Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins.Neeper M; Schmidt AM; Brett J; Yan SD; Wang F; Pan YC; Elliston K; Stern D; Shaw Department of Cellular and Molecular Biology, Merck, West Point, Pennsylvania 19486. J Biol Chem 267: 14998-5004 (1992)Advanced glycosylation end products of proteins (AGEs) are nonenzymatically glycosylated proteins which accumulate in vascular tissue in aging and at an accelerated rate in diabetes. A approximately 35-kDa polypeptide with a unique NH2-terminal sequence has been isolated from bovine lung and found to be present on the surface of endothelial cells where it mediates the binding of AGEs (receptor for advanced glycosylation end product or RAGE). Using an oligonucleotide probe based on the amino-terminal sequence of RAGE, an apparently full-length cDNA of 1.5 kilobases was isolated from a bovine lung cDNA library. This cDNA encoded a 394 amino acid mature protein comprised of the following putative domains: an extracellular domain of 332 amino acids, a single hydrophobic membrane spanning domain of 19 amino acids, and a carboxyl-terminal domain of 43 amino acids. A partial clone encoding the human counterpart of RAGE, isolated from a human lung library, was found to be approximately 90% homologous to the bovine molecule. Based on computer analysis of the amino acid sequence of RAGE and comparison with databases, RAGE is a new member of the immunoglobulin superfamily of cell surface molecules and shares significant homology with MUC 18, NCAM, and the cytoplasmic domain of CD20.
Expression of the RAGE cDNA in 293 cells allowed them to bind 125I-AGE-albumin in a saturable and dose-dependent manner (Kd approximately 100 nM), blocked by antibody to RAGE. Western blots of 293 cells transfected with RAGE cDNA probed with anti-RAGE IgG demonstrated expression of immunoreactive protein compared to its absence in mock-transfected cells. These results suggest that RAGE functions as a cell surface receptor for AGEs, which could potentially mediate cellular effects of this class of glycosylated proteins.
Expression cloning of SR-BI, a CD36-related class B scavenger receptor.Acton SL; Scherer PE; Lodish HF; Krieger M Department of Biology, Massachusetts Institute of Technology, Cambridge. J Biol Chem 269: 21003-9 (1994)Scavenger receptors are integral membrane proteins that mediate the endocytosis of modified lipoproteins. The first of these to be purified and cloned were the type I and II macrophage scavenger receptors (SR-AI and SR-AII; class A scavenger receptors). Subsequently, the cell surface protein CD36 was shown to bind oxidized low density lipoprotein (oxidized LDL). From a Chinese hamster ovary (CHO) cell variant we have cloned by expression the cDNA for a new member of the CD36 family of membrane proteins, SR-BI, whose predicted protein sequence of 509 amino acids is approximately 30% identical to those of the four previously identified family members. Both SR-BI and CD36 displayed high affinity binding for acetylated LDL with an apparent dissociation constant on the order of approximately 5 micrograms of protein/ml. The ligand binding specificities of CD36 and SR-BI, determined by direct binding or competition assays, were similar, but not identical; both bind modified proteins (acetylated LDL, oxidized LDL, maleylated bovine serum albumin), but not the broad array of other polyanions (e.g. fucoidin, polyguanosinic acid, carrageenan) which are ligands of the class A receptors.
Thus, SR-BI and CD36 define a second class of scavenger receptors, designated class B. Native LDL, which does not bind to either class A receptors or CD36, unexpectedly bound with high affinity to SR-BI. Northern blot analysis of murine tissues showed that SR-BI was most abundantly expressed in fat and was present at moderate levels in lung and liver. Furthermore, SR-BI mRNA expression was induced upon differentiation of 3T3-L1 cells into adipocytes. Thus, the tissue distribution of expression and ligand binding properties of SR-BI raise the possibility that this cell surface receptor may play an important role in lipid metabolism.
Associated Press ...Aug 20,1996
Obscure 'bad' cholesterol may wreak as much havoc as its cousin
[Apolipoprotein e4 is a risk factor for CJD; lipid peroxidation may also have a role -- webmaster]
CHICAGO -- A little-known form of "bad" cholesterol that doctors cannot yet measure reliably may cause early heart disease just as often as its better-known cousins, a study suggests. The lesser-known culprit -- called lipoprotein(a) -- may lurk in dangerously high levels in the blood of people whose other cholesterol levels appear normal on routine tests, researchers say.
Excess levels of lipoprotein(a), which are particles of protein and fat in the blood, accounted for 10 percent of all cases of premature heart disease -- those occurring before age 55 -- among the 2,191 men studied, said Dr. Andrew G. Bostom, who led the work as a research fellow for the National Heart, Lung and Blood Institute. The findings were published in the Wednesday August 21 issue of The Journal of the American Medical Association.
The study included women, but too few cases of premature heart disease developed to calculate their risk from Lp(a), presumably because estrogen protects premenopausal women from heart disease, Bostom said. Bostom said it's too early to do widespread testing for Lp(a) levels because no standardized screening exists and because even when the Lp(a) level is known, very little can now be done to modify it. Unlike other kinds of cholesterol, Lp(a) levels are 95 percent determined by genes, so drugs and changes in diet affect them very little.
The value of knowing an excess Lp(a) level is that it may warn the patient of the need for more aggressive treatment of other traits that also predict heart disease: smoking, poor diet, high blood pressure, high blood sugar and high cholesterol of the type whose levels can be altered through diet or drugs. People worried about heart disease should concentrate on those risk factors rather than worrying about Lp(a) because nothing can be done about it at present, the researchers said.
"Smoking just blows everything out of the water in terms of being a risk factor for premature coronary heart disease," Bostom said. He noted smoking accounted for 55 percent of cases of premature heart disease in the study. Abnormal levels of two better-known forms of cholesterol -- HDL, or "good" cholesterol, and total cholesterol, a combination of all forms -- each accounted for about 10 percent of premature heart disease in the study.
The participants began the study at ages 20 to 54 and were tracked for 15 years, until 1991. A total of 129 suffered premature heart disease, defined as a heart attack, poor blood flow to the heart, heart pain or sudden heart death. An expert not associated with the study, Dr. Angelo Scanu, director of the Lipid Clinic at the University of Chicago, cautioned that scientists still do not fully understand the role of Lp(a).
For example, blacks have two to three times the rate of elevated Lp(a) compared with whites, yet they do not have double to triple the prevalence of premature heart disease, Scanu said.
As many as 20 percent of people overall have elevated Lp(a) levels, but after more than 20 years of studying Lp(a), scientists still don't know which people the substance threatens and which people it doesn't, Scanu added.
Chromosome 14-encoded Alzheimer's diseaseHaltia M; Viitanen M; Sulkava R; Ala-Hurula V; Poyhonen M; Goldfarb L; Brown P; Levy E; Houlden H; Crook R; et al Department of Pathology, University of Helsinki, Finland. Ann Neurol, 36: 3, 1994 Sep, 362-7A family of Finnish descent with very-early-onset Alzheimer's disease has been identified. Genetic analysis of this family eliminated the amyloid precursor protein gene as the pathogenic locus, but strongly implicated a locus on chromosome 14q23.4 between D14S52 and D14S55. The early age at onset of the disease (average, 36 years; range, 35-39 years), the rapid progression, and the early and prominent myoclonus, while they appear to be frequent findings in the chromosome 14-encoded form of Alzheimer's disease, raised the clinical suspicion of prion disease. However, sequencing the prion gene-coding region of 2 affected members of the pedigree failed to show any abnormality. Apart from the presence of modest cortical vacuolar change, the pathological features of our index patient appeared typical of Alzheimer's disease with abundant senile plaques immunoreactive with beta-amyloid, but not with prion protein antibodies.
Apolipoprotein E and prion genotype: plaque formation and age of onset in sporadic CJDPickering-Brown SM; Mann DM; Owen F; Ironside JW; de Silva R; Roberts DA; Balderson DJ; Cooper PN Division of Neuroscience, School of Biological Sciences, University of Manchester, UK Neurosci Lett, 187: 2, 1995 Mar 3, 127-9Prion gene sequence is thought to affect the phenotypic expression of prion disease and the E2 variant of apolipoprotein E (Apo E) can be neuroprotectivein dementia. We determined codon 129 of the prion gene and the Apo E variants in Creutzfeldt-Jakob disease (CJD) using PCR and restriction digest. Wefound a significant correlation between valine at codon 129 of the prion protein gene and the presence of plaque in CJD and a later age of onset in CJD casespossessing the Apo E2 allele. This study provides further evidence that sequence variations in the prion gene can modify disease pathology and theneuroprotection afforded by Apo E2 is not confined to Alzheimer's disease.
Structure of amyloid A4-(1-40)-peptide of Alzheimer's disease.Sticht H; Bayer P; Willbold D; Dames S; Hilbich C; Beyreuther K; Frank RW; R–sch P Lehrstuhl f¸r Biopolymere, Universit”t Bayreuth, Bayreuth, Germany. Eur J Biochem, 233: 1, 1995 Oct 1, 293-8One of the principle peptide components of the amyloid plaque deposits of Alzheimer's disease in humans is the 40-amino-acid peptide beta-amyloid A4-(1-40)-peptide. The full-length A4-(1-40)-peptide was chemically synthesized and the solution structure determined by two-dimensional nuclear magnetic resonance spectroscopy and restrained molecular-dynamics calculations. Synthetic human A4-(1-40)-peptide was soluble and non-aggregating for several days in 40% (by vol.) trifluoroethanol/water. All spin systems could be unambiguously assigned, and a total of 203 sequential and medium-range cross-peaks were found in the NOESY (nuclear Overhauser enhancement spectroscopy) spectrum. Long-range NOE cross-peaks that would indicate tertiary structure of the peptide were absent. The main secondary-structure elements found by chemical-shift analysis, sequential and medium-range NOESY data, and NOE-based restrained molecular-dynamics calculations were two helices, Gln15-Asp23 and Ile31-Met35, whereas the rest of the peptide was in random-coil conformation. A similar secondary structure is suggested for the aggregation part of prions, the postulated causative agents of the transmissible spongiform encephalopathy. The sequence of the helical part of prion proteins was observed to be remarkably similar to the sequence of the helical part of human A4-(1-40)-peptide.
Human mRNA for amyloid A4 precursor of Alzheimer's disease. Kang,J., Lemaire,H.G., Unterbeck,A., Salbaum,J.M., Masters,C.L., Grzeschik,K.H., Multhaup,G., Beyreuther,K. and Muller-Hill,B. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor Nature 325 (6106), 733-736 (1987) "PID:g28526" ..."SWISS-PROT:P05067" MLPGLALLLLAAWTARALEVPTDGNAGLLAEPQIAMFCGRLNMH MNVQNGKWDSDPSGTKTCIDTKEGILQYCQEVYPELQITNVVEANQPVTIQNWCKRGR KQCKTHPHFVIPYRCLVGEFVSDALLVPDKCKFLHQERMDVCETHLHWHTVAKETCSE KSTNLHDYGMLLPCGIDKFRGVEFVCCPLAEESDNVDSADAEEDDSDVWWGGADTDYA DGSEDKVVEVAEEEEVAEVEEEEADDDEDDEDGDEVEEEAEEPYEEATERTTSIATTT TTTTESVEEVVRVPTTAASTPDAVDKYLETPGDENEHAHFQKAKERLEAKHRERMSQV MREWEEAERQAKNLPKADKKAVIQHFQEKVESLEQEAANERQQLVETHMARVEAMLND RRRLALENYITALQAVPPRPRHVFNMLKKYVRAEQKDRQHTLKHFEHVRMVDPKKAAQ IRSQVMTHLRVIYERMNQSLSLLYNVPAVAEEIQDEVDELLQKEQNYSDDVLANMISE PRISYGNDALMPSLTETKTTVELLPVNGEFSLDDLQPWHSFGADSVPANTENEVEPVD ARPAADRGLTTRPGSGLTNIKTEEISEVKMDAEFRHDSGYEVHHQKLVFFAEDVGSNK GAIIGLMVGGVVIATVIVITLVMLKKKQYTSIHHGVVEVDAAVTPEERHLSKMQQNGY ENPTYKFFEQMQN Human PreA4 gene for Alzheimer's disease A4 amyloid precursor (exon 12) (bases 1 to 439) Lemaire,H.G., Salbaum,J.M., Multhaup,G., Unterbeck,A., Bayney,R.M., Beyreuther,K. and Mueller-Hill,B. 1 ttgaatgcca tgtgcctcag ttttcacatc tgtaaaaggg agatgataat ggtacctatg 61 tcatggctct aaacgcgatc atgcacgtga aagcagttga agtcttgcct ggcagaagta 121 aatggtggct gctgctgctg ctgctgttgt gattgttgtt actcaccaaa gagatggttt 181 tgtttggttt agatgagctg cttcagaaag agcaaaacta ttcagatgac gtcttggcca 241 acatgattag tgaaccaagg atcagttacg gaaacgatgc tctcatgcca tctttgaccg 301 aaacgaaaac caccgtggag ctccttcccg tgaatggaga gttcagcctg gacgatctcc 361 agccgtggca ttcttttggg gctgactctg tgccagccaa cacagaaaac gaaggtaaga 421 gtcccctgag ccagcaagg