Alzheimer: Rejuvenating the brain's disposal system

A characteristic feature of Alzheimer's disease is the presence of so called amyloid plaques in the patient's brain -- aggregates of misfolded proteins that clump together and damage nerve cells. Researchers have now discovered a strategy to help the brain remove amyloid plaques.

A characteristic feature of Alzheimer's disease is the presence of so called amyloid plaques in the patient's brain -- aggregates of misfolded proteins that clump together and damage nerve cells. Although the body has mechanisms to dispose these aggregates, it apparently cannot keep up with the load in the diseased brain. Researchers from the German Center for Neurodegenerative Diseases (DZNE), Munich and the Ludwig Maximillian’s University (LMU) Munich have now discovered a strategy to help the brain remove amyloid plaques. More precisely: they uncovered a factor that can activate microglial cells to engulf newly forming clumps in the brain. Microglia are the scavenger cells of the brain's immune system that function in keeping the brain tidy and free of any damaging material. The work is published today in The EMBO Journal.
Plaques form when protein pieces called beta-amyloid (BAY-tuh AM-uh-loyd) clump together. Beta-amyloid comes from a larger protein found in the fatty membrane surrounding nerve cells. Beta-amyloid is chemically "sticky" and gradually builds up into plaques.

The most damaging form of beta-amyloid may be groups of a few pieces rather than the plaques themselves. The small clumps may block cell-to-cell signaling at synapses. They may also activate immune system cells that trigger inflammation and devour disabled cells.



Previous research addressing the function of microglia in Alzheimer's disease was hampered by methodological constraints. Researchers often used microglial cells cultured in a dish, but only microglia from newborn mice survive outside the body. However, young microglia is not ideal to investigate an age-related illness, especially since it was known that microglia change in the course of the disease. All in all, the role of microglia in clearing the brain of amyloid plaques was still under debate.

The research team from Munich, headed by Christian Haass and Sabina Tahirovic, devised a new tissue culture system to address these issues. The scientists took aged brain tissue from mouse model of Alzheimer's disease and co-cultured it with tissue from younger brains. They observed that, within a few days of culturing, amyloid plaques were starting to clear away.
A detailed analysis of this process revealed that microglia from the aging tissue, were engulfing the plaques on site but they received some long-distance assistance from the younger tissue in the dish. In fact, young microglia is secreting factors that helped old microglia rejuvenate, resume cell division and take up their work: clear the brain from plaques. One of the factors that reactivated aged microglia is called "granulocyte-macrophage colony stimulating factor" or GM-CSF for short. The researchers found that GM-CSF alone could do the job.



GM-CSF has previously been reported to reduce plaques and improve cognition in a mouse model of Alzheimer's disease. However, it is not yet known if GM-CSF could potentially work as a new drug for Alzheimer's disease in humans. Caution is advised, because activating microglia may also have its downsides. Microglia secreted small proteins that induce inflammatory reactions and may harm neurons. The new model system of Tahirovic, Haass and their colleagues, however, can be explored further to search for additional factors that enhance the clearance of amyloid plaques.

Story Source:
Materials provided by EMBO
Journal Reference:
Daria A, Colombo A, Llovera G, Hampel H, Willem M, Liesz A, Haass C, Tahirovic S. Young microglia restore amyloid plaque clearance of aged microglia. The EMBO Journal, 2016

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The Alzheimer

A new nasal Spray Vaccine promises to protect Against the terrible disease

Researchers are working on a nasally-delivered vaccine that promises to protect against both Alzheimer’s and Stroke, repairing vascular damage in the brain

One in eight Americans will fall prey to Alzheimer's disease at some point in their life, current statistics say. Because Alzheimer's is associated with vascular damage in the brain, many of them will succumb through a painful and potentially fatal stroke.

But researchers led by Dr. Dan Frenkel of Tel Aviv University's Department of Neurobiology at the George S. Wise Faculty of Life Sciences are working on a nasally-delivered 2-in-1 vaccine that promises to protect against both Alzheimer's and stroke. The new vaccine repairs vascular damage in the brain by rounding up "troops" from the body's own immune system.



And in addition to its prophylactic effect, it can work even when Alzheimer's symptoms are already present. The research on this new technology was recently accepted for publication in the journal Neurobiology of Aging.

A natural way to fight Alzheimer's
"Using part of a drug that was previously tested as an influenza drug, we've managed to successfully induce an immune response against amyloid proteins in the blood vessels," says Dr. Frenkel, who collaborated on this project with Prof. Howard L. Weiner of Brigham and Women's Hospital, Harvard Medical School. "In early pre-clinical studies, we've found it can prevent both brain tissue damage and restore cognitive impairment," he adds.

Modifying a vaccine technology owned by Glaxo Smith Kline, a multinational drug company, Tel Aviv University's new therapeutic approach activates a natural mechanism in our bodies that fights against vascular damage in the brain.



The vaccine, Dr. Frenkel explains, activates macrophages — large proteins in the body that swallow foreign antigens. When the vaccine activates large numbers of these macrophages, they clear away the damaging build-up of waxy amyloid proteins in our brain's vascular system.

Animal models showed that once these proteins are cleared from the brain, further damage can be prevented, and existing damage due to a previous stroke can be repaired.

A new road to an Alzheimer's cure?
Could the breakthrough lead to both a vaccine and a long-sought cure for Alzheimer's disease? "It appears that this could be the case," says Dr. Frenkel, who worked on the study with his doctoral student Veronica Lifshitz and master degree students Ronen Weiss and Tali Benromano. "We've found a way to use the immune response stimulated by this drug to prevent hemorrhagic strokes which lead to permanent brain damage," he says.

In the animal models in mice, Dr. Frenkel's team worked with MRI specialist Prof. Yaniv Assaf and his Ph.D. student Tamar Blumenfeld-Katzir of Tel Aviv University's Department of Neurobiology and then with "object recognition" experiments, testing their cognitive functioning both before and after administration of the vaccine. MRI screenings confirmed that, after the vaccine was administered, further vascular damage was prevented, and the object recognition experiments indicated that those animals treated with the new vaccine returned to normal behavior.



Dr. Frenkel believes that this approach, when applied to a human test population, will be able to prevent the downward health spiral of Alzheimer's and dementia. The vaccine could be given to people who are at risk, those who show very early symptoms of these diseases, and those who have already suffered strokes to repair any vascular damage.
So far the vaccine has shown no signs of toxicity in animal models. Dr. Frenkel is hopeful that this new approach could lead to a cure, or at least an effective treatment, for the vascular dementia found in 80% of all people with Alzheimer's.
Source : Tel Aviv University

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Can Alzheimer's disease be prevented?

New clinical studies are showing a dramatic breakthrough in the fight against Alzheimer's disease. In a model of studies, using animals that mimicked the human trials, researchers at the University of California (UC), and the School of Medicine in San Diego, reported a treatment, long-term, using a drug compound of small molecules that reduces the activity of the brain circuits stress, also significantly reduces the neuropathology of Alzheimer's disease (AD) and prevents the occurrence of cognitive impairment. These tests on neurodegenerative disease were developed using a mouse as a model.
The results are described in the publication, on internet, Alzheimer and Dementia magazine, published by: The Journal of the Alzheimer's Association.
“Alzheimer’s is a progressive brain disease that causes problems with memory, reasoning, behavior and motor skills. Symptoms of Alzheimer’s slowly worsen over time, and the disease is ultimately fatal.

Alzheimer’s is the most common form of dementia, which is defined as a loss of cognitive functioning and behavioral abilities that interferes with daily life. Other forms of dementia include vascular dementia, dementia with Lewy bodies, and frontotemporal dementia. Each of these diseases has its own set of specific symptoms.”



At this point is important to mention that the results highlight the complexity and diversity of AD, the causes appear to be a combination of genetic, lifestyle and environmental factors. Previous research has shown a link between stress modulating pathways in the brain and AD. Specifically, the release of a hormone "stress-confrontation" called Corticotropin-Releasing Factor (CRF), which is largely located in the brain and acts as a neurotransmitter / neuromodulator. This molecule is dysregulated in AD and is associated with impaired cognition and detrimental changes in the tau protein, and increases the production of fragments of amyloid beta in proteins, which are grouped and trigger neurodegenerative actions in AD.
“Our work and that of our colleagues on stress and CRF have been mechanistically implicated in Alzheimer’s disease, but agents that impact CRF signaling have not been carefully tested for therapeutic efficacy or long-term safety in animal models,” said the study’s principal investigator and corresponding author Robert Rissman, PhD, assistant professor in the Department of Neurosciences and Biomarker Core Director for the Alzheimer’s Disease Cooperative Study (ADCS).
“The novelty of this study is two-fold: We used a preclinical prevention paradigm of a CRF-antagonist (a drug that blocks the CRF receptor in brain cells) called R121919 in a well-established AD model – and we did so in a way that draws upon our experience in human trials. We found that R121919 antagonism of CRF-receptor-1 prevented onset of cognitive impairment and synaptic/dendritic loss in AD mice.”



In other words, the researchers determined that modulating the mouse brain’s stress circuitry (without actually changing the normal response) mitigated generation and accumulation of amyloid plaques widely attributed with causing neuronal damage and death. As a consequence, behavioral indicators of AD were prevented and cellular damage was reduced. The mice began treatment at 30-days-old – before any pathological or cognitive signs of AD were present – and continued until six months of age.
One particular challenge, Rissman noted, is limiting exposure of the drug to the brain so that it does not impact the body’s ability to response to stress. “This can be accomplished because one advantage of these types of small molecule drugs is that they readily cross the blood-brain barrier and actually prefer to act in the brain,” Rissman said. Drugs like R121919 were originally designed to treat generalized anxiety disorder, irritable bowel syndrome and other diseases, but failed to be effective in treating those disorders.
“Rissman’s prior work demonstrated that CRF and its receptors are integrally involved in changes in another AD hallmark, tau phosphorylation,” said William Mobley, MD, PhD, chair of the Department of Neurosciences and interim co-director of the Alzheimer’s Disease Cooperative Study at UC San Diego. “This new study extends those original mechanistic findings to the amyloid pathway and preservation of cellular and synaptic connections. Work like this is an excellent example of UC San Diego’s bench-to-bedside legacy, whereby we can quickly move our basic science findings into the clinic for testing,” said Mobley.
Rissman said R121919 was well-tolerated by AD mice (no significant adverse effects) and deemed safe, suggesting CRF-antagonism is a viable, disease-modifying therapy for AD. Rissman noted that repurposing R121919 for human use was likely not possible at this point. He and colleagues are collaborating with the Sanford Burnham Prebys Medical Discovery Institute to design new assays to discover the next generation of CRF receptor-1 antagonists for testing in early phase human safety trials.



“More work remains to be done, but this is the kind of basic research that is fundamental to ultimately finding a way to cure – or even prevent – Alzheimer’s disease,” said David Brenner, MD, vice chancellor, UC San Diego Health Sciences and dean of UC San Diego School of Medicine. “These findings by Dr. Rissman and his colleagues at UC San Diego and at collaborating institutions on the Mesa suggest we are on the cusp of creating truly effective therapies.”

Trinity Researchers Report Major breakthrough in understanding Alzheimer’s Disease

Scientists at Trinity College Dublin have shed light on a fundamental mechanism underlying the development of Alzheimer's disease, which could lead to new forms of therapy for those living with the condition.

Alzheimer's is the most common form of dementia globally and affects up to 4.5 people in USA as today. It is the fourth leading cause of death in individuals over the age of 65 and it is the only cause of death among
the top ten that cannot be prevented, cured or even slowed down.
The condition is classically associated with memory loss. However, other symptoms and warning signs include difficulty performing familiar tasks, problems with language such as forgetting phrases or words, and changes
in mood, behavior and personality.
The research, published this week in leading international journal, Science Advances, was supported by Science Foundation Ireland (SFI) and the US-based charity, Brightfocus Foundation.
Alzheimer's disease is characterized, in part, by the build-up of a small protein ('amyloid-beta') in the brains of patients. Impaired clearance of this protein appears to be a major factor in the build-up of plaques, and then
in the disease process itself. While the mode by which amyloid-beta is cleared remains unclear, it is evident that it needs to be removed from the brain via the bloodstream.
Unlike blood vessels anywhere else in the body, those in the brain have properties that strictly regulate what gets in and out of the delicate tissue - this is what is known as the blood-brain barrier (BBB). The BBB functions
as a tightly regulated site of energy and metabolite exchange between the brain tissue and the bloodstream.
"We have shown that distinct components of these blood vessels termed tight junctions are altered in Alzheimer's disease. We think that this alteration could be an entrained mechanism to allow for the clearance of toxic
amyloid-beta from the brain in those living with Alzheimer's disease," said postdoctoral researcher in Trinity's School of Genetics and Microbiology, Dr James Keaney, who spearheaded the study.
Working with the Dublin Brain Bank, which is based in Beaumont Hospital, the researchers from Trinity examined brain tissues of individuals who were affected by Alzheimer's disease during their lifetime and then compared
results to those observed in model systems in the laboratory.
Research Assistant Professor in Genetics at Trinity, Dr Matthew Campbell, added: "Our recent findings have highlighted the importance of understanding diseases at the molecular level. The concept of periodic clearance of
brain amyloid-beta across the BBB could hold tremendous potential for Alzheimer's patients in the future. The next steps are to consider how this might be achieved.
"Given the recent advances in clinical trials of anti-amyloid beta antibodies, we hope our findings may lead to improved and adjunctive forms of therapy for this devastating condition."
Source: Trinity College, Dublin