Engineered mice and Alzheimer's-like dementia

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Blocking a common immune system response cleared up plaques associated with Alzheimer's Disease and enabled treated mice to recover some lost memory, Yale University researchers report Friday in the journal Nature Medicine. Researchers hope the new approach may one day overcome one of the biggest obstacles to development of new dementia medications - the difficulty in finding drugs that can safely cross the blood-brain barrier.

The results of the research surprised the scientists working in the lab of Richard Flavell , senior author of the paper, chairman of the Department of Immunobiology at Yale and investigator with the Howard Hughes Medical Institute. Flavell's team originally thought that blocking the immune system molecule TGF-(or transforming growth factor), might actually increase the buildup of amyloid plaques associated with Alzheimer's Disease.

Earlier studies had shown that Alzheimer's patients tend to have elevated amounts of TGF-, which plays a key role in activating immune system response to injury. Some had thought the presence of the molecule was simply an attempt to quiet the inflammatory response caused by a buildup of plaque. Instead, the team found that as much as 90 percent of the plaques were eliminated from the brains of mice genetically engineered to block TGF- in the peripheral immune cells. "It was like a vacuum cleaner had removed the plaques,'' Flavell said.

When the TGF- pathway was interrupted in mice engineered to have Alzheimer's, the mice showed an improved ability to perform some tests, including navigating mazes when compared to mice without TGF- blocked. Scientists also found lower levels of other biological markers associated with the dementia. When TGF- was blocked, the immune system seemed to unleash immune cells known as peripheral macrophages. The macrophages passed through the blood-brain barrier and surrounded the neurons and plaques in the brains of mice.

"If results from our study in mice engineered to develop Alzheimer's-like dementia are supported by studies in humans, we may be able to develop a drug that could be introduced into the bloodstream to cause peripheral immune cells to target the amyloid plaques,'' said Terrence Town, lead author of the study. ...http://www.medicalnewstoday.com

Flavonoids linked to lung cancer protection amongst smokers: study

The risk of lung cancer amongst smokers may be decreased by as much as 50 per cent by an increased intake of certain antioxidant flavonoids, according to a new study from UCLA. ...http://www.nutraingredients.com

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Antipsychotics: risk of death and stroke in people with dementia

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Alzheimer's Society comment on new research showing that short term use of antipsychotic drugs more than triple the risk of a serious event causing hospitalisation or death in people with dementia living in the community. This comprehensive study highlights the life-threatening effects antipsychotics have on people with dementia and reveals that people in the community are at greater risk than those in nursing homes.

Antipsychotics double risk of death and triple risk of stroke in people with dementia, yet up to 105,000 people with dementia in the UK are inappropriately prescribed them as a quick fix for treating challenging behaviour, such as aggression and agitation. Urgent action is needed to ensure these dangerous drugs are always a last resort. Safe, effective alternatives are available; Alzheimer's Society research shows specialist dementia training for care home staff can reduce the use of antipsychotics by up to 50%. Antipsychotics should only be used in extreme circumstances, when all alternatives have failed and for no more than 12 weeks, whilst a care plan is put into place. ...http://www.medicalnewstoday.com

Beta-carotene effective as sunburn protector: meta-analysis

Oral supplements of beta-carotene may protect against sunburn, and the longer the supplementation period the greater the protection, says a new meta-analysis.

...http://www.nutraingredients.com

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NSAIDs in lowering the risk of Alzheimer's

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Different types of non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen, and aspirin, appear to be equally effective in lowering the risk of Alzheimer's disease, according to the largest study of its kind published in the May 28, 2008, online issue of Neurology®, the medical journal of the American Academy of Neurology. Experts have debated whether a certain group of NSAIDs that includes ibuprofen may be more beneficial than another group that includes naproxen and aspirin.

Using information from six different studies, researchers examined data on NSAID use in 13,499 people without dementia. Over the course of these six studies, 820 participants developed Alzheimer's disease.

Researchers found that people who used NSAIDs had 23 percent lower risk of developing Alzheimer's disease compared to those who never used NSAIDs. The risk reduction did not appear to depend upon the type of NSAID taken.

"This is an interesting finding because it seems to challenge a current theory that the NSAID group which includes ibuprofen may work better in reducing a person's risk of Alzheimer's," said study author Peter P. Zandi, PhD, with Johns Hopkins Bloomberg School of Public Health in Baltimore, MD. "The NSAID group that includes ibuprofen was thought to target a certain type of plaque in the brain found in Alzheimer's patients. But our results suggest there may be other reasons why these drugs may reduce the risk of Alzheimer's."

The study's lead author Chris Szekely, PhD, with Cedars Sinai Medical Center in Los Angeles, says the discrepancy between studies such as this one and the negative clinical trials of NSAIDs in treatment or prevention of Alzheimer's need to be further explored.

Data used in the study were collected with support from the National Institutes of Health and the Canadian Institutes of Health Research.

The American Academy of Neurology, an association of more than 21,000 neurologists and neuroscience professionals, is dedicated to improving patient care through education and research. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as stroke, Alzheimer's disease, epilepsy, Parkinson's disease, and multiple sclerosis. ...http://www.medicalnewstoday.com

Failure to publish research retards probiotic progress

The failure to publish clinical studies demonstrating the effectiveness of certain probiotic strains to reduce the symptoms of bacterial vaginosis is bordering on scientific negligence, according to Gregor Reid, PhD, an expert in the area. ...http://www.nutraingredients.com

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Hippocampal place cells: a potential Alzheimer's therapies ?

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Alzheimer's disease (AD) is associated with progressive memory decline. Hippocampal place cells are a well understood candidate for the neural basis of one type of memory in rodents; these cells identify the animal's location in an environment and are crucial for spatial memory and navigation. We have recorded place cells in the Tg2576 mouse model of AD, and we report that aged (16 mo) but not young (3 mo) transgenic mice show degraded neuronal representations of the environment. The level of place cell degradation correlates with the animals' (poorer) spatial memory as tested in a forced-choice spatial alternation T-maze task and with hippocampal, but not neocortical, amyloid plaque burden. Place cell recording provides a sensitive assay for measuring the amount and rate of functional deterioration in animal models of dementia as well as providing a quantifiable physiological indication of the beneficial effects of potential therapies. ...Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0802908105

Apple polyphenols may protect stomachs from aspirin damage

Polyphenol extracts from apples may protect stomachs from ulcers and other complications associated with aspirin, suggests a new animal study from Italy. ...http://www.nutraingredients.com

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Is this gene causing the Alzheimer's?

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A new study has identified the cause of late-onset Alzheimer's disease in several large families in which many siblings suffer from the disease. The gene, known as TRPC4AP on chromosome 20, is involved with calcium regulation. It is known that when calcium levels are not carefully controlled, cells can die, leading to the onset of disease.

Alzheimer's disease is a complex progressive neurodegenerative disorder in which patients suffer from profound cognitive decline. There is no known cure for the disease, but treatment delays its progression. Its cause is currently unknown, though family history has been identified as an important risk factor. Heritability for the disease has been estimated at 79 percent, with no susceptibility difference found between men and women. Many genetic variants of the disease have been identified; however replication in other samples of Alzheimer's patients has been limited.

In research conducted at the Medical College of Georgia and the VA Medical Center in Augusta, Ga., two large families with late-onset Alzheimer's disease were enrolled in a DNA Bank. Both families had 15 siblings, five of whom were affected with the disease. Moreover, in one family, several of the father's siblings also were affected and were still living, a rarity among study populations of late-onset Alzheimer's patients. Blood samples were collected from all siblings, the parent's siblings, as well as the spouses and children for genetic study.

Dr. Shirley Poduslo and her staff used high-tech SNP microarrays, which display the genetic structure of DNA, with the patients and control spouses to identify the location of the gene causing the disease in these families. SNPs, or single nucleotide polymorphisms, are single base changes in gene structure which are found throughout DNA. Next they analyzed additional SNPs in the DNA from each family member. They found that all of the affected patients from both families had the same pattern of SNPs, which were different from the control spouses. Dr. Poduslo and her lab then analyzed DNA from the Alzheimer's patients and controls in the DNA Bank. They found that 36 percent of the patients had the same pattern of SNPs as found in the patients in the families. "The use of extended pedigrees is vital for genetic studies. The next step will be to identify the exact mutation in this gene which is causing the disease," says Poduslo. "The DNA is currently being sequenced to find this mutation."

These findings have opened a new line of research that may potentially lead to understanding what causes Alzheimer's. Future studies of this protein may potentially lead to new drug treatments. "The long term significance will be to understand the mechanism of the disease so that more effective drugs can be designed to slow the progression of the disease, delay the onset, identify patients early in the disease course and, hopefully, someday to keep this dreadful disease from occurring," says Poduslo. ...http://www.medicalnewstoday.com

Italy number one for antioxidant-rich kiwi supply

Supplies to food and supplements makers for the fruit that packs a powerful antioxidant punch continue to grow as Italy, the world's largest producer of kiwis, reports strong production figures for 2007. ...http://www.nutraingredients.com

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Cu imbalance: a therapeutic target for Alzheimer's

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In Alzheimer's disease there is abnormal brain copper distribution, with accumulation of copper in amyloid plaques and a deficiency of copper in neighbouring cells. Excess copper inhibits Abeta (amyloid beta-peptide) production, but the effects of deficiency have not yet been determined. We therefore studied the effects of modulating intracellular copper levels on the processing of APP (amyloid precursor protein) and the production of Abeta. Human fibroblasts genetically disposed to copper accumulation secreted higher levels of sAPP (soluble APP ectodomain)alpha into their medium, whereas fibroblasts genetically manipulated to be profoundly copper deficient secreted predominantly sAPPbeta and produced more amyloidogenic beta-cleaved APP C-termini (C99). The level of Abeta secreted from copper-deficient fibroblasts was however regulated and limited by alpha-secretase cleavage. APP can be processed by both alpha- and beta-secretase, as copper-deficient fibroblasts secreted sAPPbeta exclusively, but produced primarily alpha-cleaved APP C-terminal fragments (C83). Copper deficiency also markedly reduced the steady-state level of APP mRNA whereas the APP protein level remained constant, indicating that copper deficiency may accelerate APP translation. Copper deficiency in human neuroblastoma cells significantly increased the level of Abeta secretion, but did not affect the cleavage of APP. Therefore copper deficiency markedly alters APP metabolism and can elevate Abeta secretion by either influencing APP cleavage or by inhibiting its degradation, with the mechanism dependent on cell type. Overall our results suggest that correcting brain copper imbalance represents a relevant therapeutic target for Alzheimer's disease. ...http://www.ncbi.nlm.nih.gov/pubmed

News briefs: healthy and premium chocolate launches

In recent years there has been an increasing trend towards healthy and premium confectionery products, aimed at making consumers feel better about the treats they eat and giving them a taste of luxury and sophistication. ...http://www.nutraingredients.com

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Apoptotic mechanisms in Alzheimer

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Although neuronal apoptosis in Alzheimer's disease is generally interpreted as the consequence of the toxicity of extracellular beta-amyloid (Abeta) peptide aggregates, some experimental results provide evidence that the Abeta overproduction can be the result of a primary neuronal degeneration. As platelets are considered a good model where to study proteolytic processing of the amyloid precursor protein (APP), we exposed platelets to the proapoptotic agent ionomycin and analyzed Abeta40 and Abeta42 levels in the intracellular and extracellular compartments. The activation of apoptotic pathways in platelets has been verified by mitochondrial membrane depolarization, exposure of phosphatidylserine, protease activation and morphological changes. A significative increase in intraplatelet Abeta40, but not Abeta42, was observed after 10 min treatment with ionomycin. Thus, the activation of apoptotic pathways in platelets determines an altered processing of APP leading to elevated levels of intracellular Abeta40. The specific intracellular production of Abeta40 represents a potential threat to the cells since very high local Abeta40 concentration increases the risk of its aggregation and toxicity. As a result, Abeta40 might be dangerous even before it becomes secreted rendering neurons highly vulnerable. ...http://www.ncbi.nlm.nih.gov/pubmed

The GSK weight loss wake-up call

GlaxoSmithKline's petition to the Food and Drug Administration (FDA) to ban dietary supplements from making weight loss claims, has opened a cupboard and only the deluded would deny the presence of one or two skeletons rattling around in there.

...http://www.nutraingredients.com

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New lines of research into Alzheimer's disease

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A number of chronic diseases are in fact caused by one or more infectious agents. For example, stomach ulcers are caused by Helicobacter pylori, chronic lung disease in newborns and chronic asthma in adults are both caused by Mycoplasmas and Chlamydia pneumonia, while some other pathogens have been associated with atherosclerosis. The realization that pathogens can produce slowly progressive chronic diseases has opened new lines of research into Alzheimer's disease.

Alzheimer's disease (AD), the most frequent cause of dementia, is a form of amyloidosis. It has been known for a century that dementia, brain atrophy and amyloidosis can be caused by chronic bacterial infections, namely by Treponema pallidum in the atrophic form of general paresis in syphilis. Bacteria and viruses are powerful stimulators of inflammation. It was suggested by Alois Alzheimer and his colleagues a century ago that microorganisms may be contributors in the generation of senile plaques in AD. The fact that pathogens may suppress, subvert or evade host defenses and establish chronic or latent infection has received little attention in the past. During infection, active oxygen and nitrogen species generated by inflammatory cells may cause DNA damage, induce apoptosis, and modulate enzyme activities and gene expression. Depending upon the biology of the pathogen and the host defense mechanisms the organism can persist in the infected tissues and cause chronic inflammation and amyloid deposition. The outcome of infection is as much determined by the genetic predisposition of the patient as by the virulence and biology of the infecting agent. Environmental factors and nutrition are critical determinants of disease expression as well.

In this special issue a series of reviews draws attention to both historic and recent observations related to this emerging field of AD research. The first review shows the importance of chronic inflammation in AD, followed by three articles presenting evidence on the involvement of spirochetes, Chlamydia pneumoniae and Herpes simplex virus type 1 in AD. These are followed by a review of amyloid proteins, which occur in many cellular forms in Eukaryotes and Prokaryotes. The link between several viral and bacterial infections and the most significant genetic factor for AD, APOE a4, is discussed in the next review. The link between excessive or misplaced iron and a variety of neurodegenerative diseases and infection is reviewed in the final article.

According to Miklossy and Martins, "The historic and new observations reviewed in this special issue clearly show that high priority should be given for further research in this field as it may have major implications for public health, treatment, and prevention as adequate anti-bacterial and anti-viral drugs are available. Treatment of a bacterial infection and associated viral infection may result in regression and, if started early, prevention of disease. The impact on reducing healthcare costs would be substantial." ...http://www.spectroscopynow.com

Sea buckthorn could have liver benefits, say scientists
A new study on sea buckthorn has found that the extract may ward off liver disease, leading researchers to conclude that it could be incorporated into a nutraceutical food or supplement targeting the condition. ...http://www.nutraingredients.com

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Zinc in Alzheimer's disease

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X-Ray absorption spectroscopy, nuclear magnetic resonance spectroscopy, and together quantum mechanics calculations could help researchers pin down the role of metal ions in the formation of the beta-amyloid plaques present in Alzheimer's disease.

More than twenty diseases, including Alzheimer's disease, involve the production of errant forms of various natural proteins and peptides in the brain and other tissues. The process of amyloidosis in which these peptides and proteins switch from a physiological soluble configuration to an insoluble and pathological has been well studied. It is well known that amyloidosis leads to the formation of harmful plaques.

However, while plaques are known to contain fairly high concentrations of transition metal elements, including copper, iron, and zinc, the role of these metals in plaque formation is not yet fully understood. Indeed, the presence of such metals at higher than normal levels may be a cause or an effect. New evidence from the use of metal-grabbing chelating agents, which have been found to solubilize amyloid aggregates would suggest the former, particular with regards copper and zinc in Alzheimer's disease. Such a finding points to possible new treatments for this disease but also raises new questions about the precise role of metal ions in plaque formation.

Now, Velia Minicozzi, Sylvia Morante, Gian Carlo Rossi, and Francesco Stellato of the Department of Physics at the University of Rome Tor Vergata, Italy, Nils Christian of Humboldt University, in Berlin, and Karl Jansen of NIC DESY-Zeuthen, Germany, have used a raft of analytical techniques together with quantum mechanics to turn a spotlight on this role.

The main protein-like component present in the amyloid plaques found in the brains of patients with Alzheimer's disease is the beta-amyloid peptide. This material originates from the splitting of Amyloid Precursor Protein (APP), which itself is a 770 amino acid transmembrane protein coded by chromosome 21. The researchers point out that there are several so-called secretase enzymes that can cleave APP. When two secretases work together harmless cleavage products are formed. However, an alternative cleavage pathway results in the harmful form of the protein.

The researchers add that recent experimental evidence suggests that these peptides can complex with both copper and zinc ions, and there are hints that these two metals play counteractive roles, with copper inhibiting the tendency of zinc to induce protein aggregation. Of course, both copper and zinc are essential to several metabolic processes in the brain and elsewhere in the body, so excluding them is not an option.

However, these metals must be present in specific forms to function and not to trigger pathological effects. Copper, iron, and zinc are all present at fairly high concentrations in the healthy brain and evidence suggests that the breakdown of regulation of metal trafficking across the blood-brain barrier is associated with age-related neurodegenerative diseases. Other researchers have hinted that copper and zinc may lead to the precipitation process that forms amyloid plaques.

The German-Italian team have used modern spectroscopic techniques and numerical first principle simulations to investigate the physicochemical basis of such amyloid aggregation. Specifically, they turned to X-ray absorption spectroscopy to successfully reveal the atomic structure around the metal binding sites in amyloid peptides complexed with either copper or zinc ions. NMR spectroscopic information then showed them the amino acid residues that are coordinated to the metals.

The experiments with copper show that three histidine residues in the protein sequence are involved, whereas zinc coordination apparently involves four histidines. This, the team explains, suggests that zinc is somehow involved in promoting the aggregation of amyloid sequences into fibrous plaques.

In order to find a theoretical basis for this assertion, the team turned to first principle ab initio molecular dynamics simulations, which they found fitted nicely with the NMR and X-ray data. "Although we are still far from a clear understanding of the role of metals in protein misfolding and/or aggregation, experimental and theoretical studies, not unexpectedly, seem to point to a rather complicated structural scenario," the researchers say. http://www.spectroscopynow.com

Sea buckthorn could have liver benefits, say scientists
A new study on sea buckthorn has found that the extract may ward off liver disease, leading researchers to conclude that it could be incorporated into a nutraceutical food or supplement targeting the condition. ...http://www.nutraingredients.com

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