Clarified the role of calcium in familial Alzheimer's disease, on new Therapeutics

Now, on the same team, under the direction of J. Kevin Foskett, PhD, Professor of Physiology and a student, Dustin shilling, has determined that the hyperactivity of the calcium channels alleviated FAD-like symptoms in mice models of the disease to suppress. Their findings appear this week in the Journal of neuroscience.

Current therapies for Alzheimer's disease are drugs, the treatment of the symptoms of cognitive and dementia and medication, the pathology to treat Alzheimer's disease are experimental. These new observations suggest that approaches by modulating calcium signaling could be examined on the basis of, Foskett says.

The two proteins called, PS1 and PS2 (Presenilin 1 and 2), interact with a calcium release channel, the inositol-Trisphosphate receptor (IP3R), in the endoplasmic reticulum. Mutant PS1 and PS2 to increase the activity of the IP3R, in turn increased calcium in the cell. "We set out to answer the question: is increased calcium signal by the Presenilin-IP3R interaction, at the development of familial Alzheimer's disease symptoms, including dementia and cognitive deficits?" Foskett says. "" "And with views of the results of these experiments, the answer is a clear 'Yes.'"

Robust phenomenon

Excessive intracellular calcium signaling is a robust phenomenon seen in cells expressing FAD verursachender mutant Presenilins, in both human cells in culture and in mice. The team put two BLAND looking mouse models for these connections. In particular, they found that this receptor in the brain, to 50 percent signals in neurons of the cortex reduce the expression of the IP3R1, the dominant form and hippocampus in both mouse models normalized observed excessive calcium.

In addition observed with 3xTg mouse-animals FAD mutation containing Presenilin 1 with one, as well as the mutated human Tau protein and APP gene expression gebracht-- the team that the reduced expression of IP3R1 deeply amyloid plaque accumulation in brain tissue and Hyperphosphorylation of Tau protein, a decreased biochemical hallmarks of advanced Alzheimer's disease. Reduced expression of IP3R1 saved also defective electrical signalling in the memory deficits in the 3xTg mice, and hippocampus, as well as conduct tests measured.

"Our results show that excessive calcium signaling, the Presenilin mutations in familial Alzheimer's disease is, is mediated by the IP3R and contributes to the symptoms of illness in animals", Foskett says. "With this, you know now the IP3 pathway could accommodate a potential therapeutic target molecule for patients mutations in the Presenilins in connection with AD are considered."

The hypothesis of "Calcium dysregulation"

"The" calcium dysregulation "hypothesis for inherited, early onset familial Alzheimer's disease by früheren research results in the laboratory Foskett proposed. Alzheimer's disease affects more than 5 million Americans, 5 percent who have familial form. The hallmark of the disease is the accumulation of tangles and plaques of amyloid beta protein in the brain.

"The ' amyloid hypothesis", which postulates, that the primary defect is an accumulation of toxic amyloid in the brain has long used, to explain the cause of Alzheimer's disease "Foskett says. 2008 neuron study the cells that the disease-causing mutant showed in his laboratory carried out of PS1 form processing of amyloid-beta that depends on the interaction of the IP3R PS proteins, increased. This observation combines dysregulation of calcium within cells with the production of amyloid, a characteristic feature in the brains of people with Alzheimer's disease.

Clinical studies for AD have set up largely in the reducing amyloid in the brain. So far, says Foskett, these studies have non-therapeutic benefits to demonstrate. One idea is that the intervention in the disease process started too late. Accordingly, clinical trials in progress using anti-amyloid FAD asymptomatic patients now because it is known that they will eventually develop the disease while predicting who will develop the common form of AD is much less certain.

"There was an assumption that FAD simply display with an earlier, more aggressive occur, is," Foskett says. "But we do know whether the etiology of the FAD pathology is identical to that for general viewing. The relevance of the search results for the understanding of the common AD is not so clear. It is important, in my opinion is to recognize that the AD could be a range of diseases, lead together end-stage diseases. "FAD could therefore an orphan disease, and it is important to effective treatments, especially for these patient-those who are on the IP3R and calcium signal."

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Modified stem cells offer potential pathway to treat Alzheimer's disease

Alzheimer's disease, one of the most common forms of dementia, is associated with accumulation of the protein amyloid-beta in the brain in the form of plaques. While the search continues for a viable treatment, scientists are now looking into non-pharmaceutical ways to slow onset of this disease.

One option being considered is increasing the production of the enzyme neprilysin, which breaks down amyloid-beta, and shows lower activity in the brains of people with Alzheimer's disease. Researchers from UC Irvine investigated the potential of decreasing amyloid-beta by delivering neprilysin to mice brains.

"Studies suggest that neprilysin decreases with age and may therefore influence the risk of Alzheimer's disease," said Mathew Blurton-Jones, an assistant professor of neurobiology & behavior. "If amyloid accumulation is the driving cause of Alzheimer's disease, then therapies that either decrease amyloid-beta production or increase its degradation could be beneficial, especially if they are started early enough."

The brain is protected by a system called the blood-brain-barrier that restricts access of cells, proteins, and drugs to the brain. While the blood-brain-barrier is important for brain health, it also makes it challenging to deliver therapeutic proteins or drugs to the brain. To overcome this, the researchers hypothesized that stem cells could act as an effective delivery vehicle. To test this hypothesis the brains of two different mouse models (3xTg-AD and Thy1-APP) were injected with genetically modified neural stem cells that over-expressed neprilysin. Most studies up to now have only looked into a single model, and there has been found to be variation in results between models.

These genetically modified stem cells were found to produce 25-times more neprilysin than control neural stem cells, but were otherwise equivalent to the control cells. The genetically modified and control stem cells were then transplanted into the hippocampus or subiculum of the mice brains -- two areas of the brain that are greatly affected by Alzheimer's disease. The mice transplanted with genetically modified stem cells were found to have a significant reduction in amyloid-beta plaques within their brains compared to the controls. The effect remained even one month after stem cell transplantation. This new approach could provide a significant advantage over unmodified neural stem cells because neprilysin-expressing cells could not only promote the growth of brain connections but could also target and reduce amyloid-beta pathology.

Before this can be investigated in humans, more work needs to be done to see if this affects the accumulation of soluble forms of amyloid-beta. Further investigation is also needed to determine whether this new approach improves cognition more than the transplantation of un-modified neural stem cells.

"Every mouse model of Alzheimer's disease is different and develops varying amounts, distribution, and types of amyloid-beta pathology," Blurton-Jones said. "By studying the same question in two independent transgenic models, we can increase our confidence that these results are meaningful and broadly applicable to Alzheimer's disease. But there is clearly a great deal more research needed to determine whether this kind of approach could eventually be translated to the clinic."

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Gene variant puts women at higher risk of Alzheimer's than it does men, study finds

The scientists arrived at their findings by analyzing data on large numbers of older individuals who were tracked over time and noting whether they had progressed from good health to mild cognitive impairment -- from which most move on to develop Alzheimer's disease within a few years -- or to Alzheimer's disease itself.

The discovery holds implications for genetic counselors, clinicians and individual patients, as well as for clinical-trial designers. It could also help shed light on the underlying causes of Alzheimer's disease, a progressive neurological syndrome that robs its victims of their memory and ability to reason. Its incidence increases exponentially after age 65. An estimated one in every eight people past that age in the United States has Alzheimer's. Experts project that by mid-century, the number of Americans with Alzheimer's will more than double from the current estimate of 5-6 million.

According to the Alzheimer's Association, it is already the nation's most expensive disease, costing more than $200 million annually. (The epidemiology of mild cognitive impairment is fuzzier, but this gateway syndrome is clearly more widespread than Alzheimer's.)

The number of women with Alzheimer's far exceeds that of men with the condition. That's partly because women on average live longer than men. But greater longevity explains only part of women's increased susceptibility to Alzheimer's. "Even after correcting for age, women appear to be at greater risk," said Michael Greicius, MD, assistant professor of neurology and neurological sciences and medical director of the Stanford Center for Memory Disorders.

Greicius was the senior author of a study, to be published April 14 in the Annals of Neurology, in which he and his colleagues analyzed records on more than 8,000 people, most of them older than 60, who have been monitored over time at any one of about 30 Alzheimer's centers nationwide. Postdoctoral scholar Andre Altmann, PhD, was the lead author.

The records were stored in two large, publicly available repositories. In one, the researchers analyzed clinical assessments of 5,000 people whose test results were normal at the outset and 2,200 people who had initially showed signs of mild cognitive impairment. In both groups, being an ApoE4 carrier increased the likelihood of Alzheimer's disease, as expected. But a closer look revealed that among those who initially tested normal, this increased risk was only marginal for men, whereas women who carried the ApoE4 variant had close to twice the likelihood of progressing to mild cognitive impairment or Alzheimer's disease as those who didn't.

"Our study showed that, among healthy older controls, having one copy of the ApoE4 variant confers a substantial Alzheimer's disease risk in women, but not in men," Greicius said.

The second repository holds imaging data and measurements of several biochemical substances from spinal fluid that can serve as useful biomarkers of impending mild cognitive impairment and eventual Alzheimer's disease. Analysis of 1,000 patients' records from this database not only confirmed ApoE4's differential effect on women versus men, but also yielded clues that may help investigators begin to explore, and perhaps someday explain, the molecular mechanisms linking ApoE4 to Alzheimer's disease, Greicius said.

The ApoE gene is a recipe for a protein important for shuttling fatty substances throughout the body. This is particularly important in the central nervous system, as brain function depends on rapid rearrangement of such fatty substances along and among nerve cell membranes. The ApoE gene comes in three varieties -- ApoE2, ApoE3 and ApoE4 -- depending on inherited variations in the gene's sequence. As result, the protein that the gene specifies also comes in three versions, whose structures and fatty-substance-shuttling performance differ.

Most people carry two copies of the ApoE3 gene variant (one from each parent). But about one in five people carries at least one copy of ApoE4, and a small percentage have two ApoE4 copies. Numerous studies going back to the early 1990s have confirmed that ApoE4 is a key risk factor for Alzheimer's disease, with a single copy of ApoE4 increasing that risk twofold or fourfold. Carrying two copies confers 10 times the risk of Alzheimer's.

One of those many studies, published in 1997 in The Journal of the American Medical Association, suggested that female ApoE4 carriers are more at risk for Alzheimer's than male carriers are. But for various reasons, that study wasn't followed up, and both clinicians and scientists designing clinical trials tend to dismiss this distinction to this day, Greicius said. "I'd been practicing for five years before I ever heard of this paper, which had essentially been ignored for 10 years already," he said.

But on unearthing the 1997 paper, Greicius became curious. In 2012, an imaging study by his group showed provocative differences in brain function in female versus male ApoE4 carriers even when they were still completely asymptomatic. "Brain connectivity in the ApoE4 men didn't differ much from normal. But connectivity in the ApoE4 women did," he said. "That convinced me that this is a real phenomenon."

The pooled data of numerous dedicated Alzheimer's centers continuously accumulates, yielding ever-larger population samples for enterprising researchers to mine. There lies the beauty of the large government- and industry-supported repositories to which Greicius and his team turned.

Drug developers designing clinical trials for Alzheimer's are already paying plenty of attention to whether or not their trial participants carry a copy of the ApoE4 variant, as previous trials have showed a differential effect on carriers versus noncarriers. Greicius said they would do well also to differentiate between a candidate drug's effect on male versus female ApoE4 carriers. Meanwhile, basic researchers can take a cue from his findings and ask themselves, "Why the difference?" The effort to answer that question may reveal an important molecular mechanism, or set of them, that explains the differential effect. "Now we can work toward understanding the cause of this sex difference, which may reveal new potential drug targets, "Altmann said.

Greicius, who in addition to his research spends about one-fifth of his time seeing patients, said that the differential male/female ApoE4 effect implies that clinicians need to take different approaches to patients with this gene variant, depending on their sex. "These days, a lot of people are getting genotyped either in the clinic or commercially. People come to me and say, 'I have an ApoE4 gene, what should I do?' If that person is a man, I would tell him that his risk is not increased much if at all. If it's a woman, my advice will be different."

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New mouse model could revolutionize research in Alzheimer's disease

Unfortunately, it has proven very difficult to develop drugs capable of ameliorating the disease. After a tremendous burst of progress in the 1990s, the pace of discoveries has slowed. Dr. Saido believes that part of the difficulty is the inadequacy of current mouse models to replicate the real conditions of Alzheimer's disease and allow an understanding of the underlying mechanisms that lead to neurodegeneration. In fact, much of the research in Alzheimer's disease over the past decade may be flawed, as it was based on unrealistic models.

The problem with older mouse models is that they overexpress a protein called amyloid precursor protein, or APP, which gives rise to the amyloid-beta (Abeta) peptides that accumulate in the brain, eventually leading to the neurodegeneration that characterizes Alzheimer's disease. However, in mice the overexpression of APP gives rise to effects which are not seen in human Alzheimer's disease.

For example, the APP mutant mice often die of unknown causes at a young age, and the group believes this may be related to the generation of toxic fragments of APP, such as CTF-beta. In addition, some of the fragments of APP could be neuroprotective, making it difficult to judge whether drugs are being effective due to their effect on Abeta peptides, which are known to be involved in human AD, or whether it is due to other effects that would not be seen in human disease. In addition, the gene for expressing APP is inserted in different places in the genome, and may knock out other genes, creating artifacts that are not seen in humans.

With this awareness, more than a decade ago Dr. Saido launched a project to develop a new mouse model that would allow more accurate evaluation of therapies for the disease. One of the major hurdles involved a part of the gene, intron 16, which they discovered was necessary for creating more specific models.

The first mice model they developed (NL-F/NL-F) was knocked in with two mutations found in human familial Alzheimer's disease. The mice showed early accumulation of Abeta peptides, and importantly, were found to undergo cognitive dysfunction similar to the progression of AD seen in human patients. A second model, with the addition of a further mutation that had been discovered in a family in Sweden, showed even faster initiation of memory loss.

These new models could help in two major areas. The first model, which expresses high levels of the Abeta peptides, seems to realistically model the human form of AD, and could be used for elucidating the mechanism of Abeta deposition. The second model, which demonstrates AD pathology very early on, could be used to examine factors downstream of Abeta-40 and Abeta-42 deposition, such as tauopathy, which are believed to be involved in the neurodegeneration. These results may eventually contribute to drug development and to the discovery of new biomarkers for Alzheimer's disease. The group is currently looking at several proteins, using the new models, which have potential to be biomarkers.

According to Dr. Saido, "We have a social responsibility to make Alzheimer's disease preventable and curable. The generation of appropriate mouse models will be a major breakthrough for understanding the mechanism of the disease, which will lead to the establishment of presymptomatic diagnosis, prevention and treatment of the disease."

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No evidence of Alzheimer's disease related changes in young people carry genetic risk factors

Of the apolipoprotein (ApoE) ?4 allele are at increased risk of the development of late onset Alzheimer's disease (AD), develop AD at an earlier age and experience a more severe cognitive decline and shorter survival time. The ?4 allele has been linked to the severity of the hippocampal atrophy and pathological changes in the cerebral cortex. ?2 allele is thought to exercise protection against the disease.

"Atrophy of the hippocampus, a region of the brain crucial is a common feature of the display for storage, although it can be demonstrated in the asymptomatic persons as well as healthy adults carrier of the ?4 ApoE allele", said Andy Simmons, PhD, of the Department of neuroimaging of the Institute of Psychiatry of at King's College London. "If young people manifest early changes genetically at risk for AD an important question for the procedures or treatments designed to slow or the progression of the disease keeps interested."

To resolve the question, 1412 teenagers underwent MRI imaging and had tested blood samples for DNA analysis to determine their ApoE status. "In contrast to some recent studies no hippocampal volume differences between carrier and carrier of the ApoE-?4 all Elle observed", said Dr. Simmons. The investigators also other possible changes, such as hippocampal asymmetry or saw gene dose-dependent effects on volume, but could find no associations with genetic status.

In addition to structural changes in patients with AD show in the brain usually an increase in the brain strain of amyloid-ß (insoluble) peptides and a decrease in the cerebrospinal fluid (CSF) concentration of insoluble peptides. Similar changes can be found in almost all people with mild cognitive impairment risk conversion to AD. "This changes the earliest diagnostic tools in AD, dar", explains Professor Dr. med. Piotr Lewczuk, head of the laboratory of clinical neurochemistry, and neurochemical dementia diagnosis at the University Clinic for Psychiatry and psychotherapy, Universittsklinikum Erlangen, Friedrich-Alexander University Erlangen Board. Because to a certain extent, also changes the concentrations of insoluble peptide in the blood are observed, his research group investigates differences in the plasma levels of insoluble peptides among young adults e4, e3 and e2 providers.

To determine whether these changes are associated AD available at an early age before clinical symptoms are visible, investigators measured insoluble peptide concentration in the plasma of 175 cognitively normal young adults. 40 employees (22.9%) had at least one e4 allele and were the e3/e3 genotype had "endangered" for AD, 111 (63.4%) and were called "neutral" and 24 (13.7%) in the "protected: Group had at least one e2 allele."

The investigators measured four insoluble peptide and determined that no significant differences in any of the insoluble peptide plasma levels were found between the three genetic groups.

"The lack of differences of the insoluble concentration reported in this study between the groups with and without increased genetic risk for AD does not mean that the ongoing preclinical Neurodegeneration in all young subjects, can be completely excluded", says Dr. Lewczuk. He also notes that approximately 40% of AD patients of not bearing the e4 allele are. He considers, however, that findings of hippocampal volume and its study of plasma concentrations set Dr. Simmons insoluble near, that the AD-suggestive changes maybe 20-30 years before the onset of clinical symptoms, but probably not before start most.

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Caffeine against Alzheimer's disease? Proven positive effect on the Tau buildup

Tau deposits, along with beta-amyloid plaques are the characteristic features of Alzheimer's disease. These protein deposits to interfere with the communication of nerve cells in the brain and contribute to its degeneration. Despite intensive research, no drug is until today what can prevent damage thereby. Based on the findings of Prof. Dr. Christa Mller at the University of Bonn, Dr. David Blum and her team a new class can be developed now of drugs for the treatment of Alzheimer's disease.

Caffeine, an adenosine receptor antagonist blocked various receptors in the brain that are activated by adenosine. First results of the team of scientists had already indicated that the blockade of A2A adenosine receptor subtype could in particular an important role. Initially developed Prof. Mller and her colleagues an A2A antagonist in the form of high-purity and water soluble (MSX-3). This connection had fewer side effects than caffeine, as it blocks only the A2A adenosine receptor subtype, and at the same time, it is much more effective. Over several weeks, the researchers altered then genetically treated mice with the A2A antagonists. The mice had a modified Tau protein, which leads without therapy, the early development of Alzheimer's disease symptoms.

When compared to a control group, which received only a placebo, reached the treated animals significantly better on memory tests. The A2A antagonist shows positive impact in particular on spatial memory. In addition, an improvement showed the pathogenic processes in the hippocampus, is the place of memory in rodents.

"We went a good step forward," says Prof. Mller. "The results of the study are really promising, as we demonstrate for the first time were that A2A adenosine receptor antagonists have very positive effects in an animal model simulation of Hallmark characteristics and progression of the disease." And the side effects are low."

Now want researchers to test the A2A antagonists in additional animal models. If the results are positive, a clinical study can be carried out. "Patience is needed until A2A adenosine receptor antagonists as new Therapeutics for Alzheimer's disease are approved. But I am optimistic that clinical trials are conducted, "says Prof. Mller.

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