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Dementia

Liver ‘may play key role in Alzheimer’s’

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Amyloid protein made in the liver can cause neurodegeneration in the brain, according to a new study.

Since the protein is thought to be a key contributor to development of Alzheimer’s disease (AD), the results suggest that the liver may play an important role in the onset or progression of the disease.

Deposits of amyloid-beta (A-beta) in the brain are one of the pathological hallmarks of AD and are implicated in neurodegeneration in both human patients and animal models of the disease.

But A-beta is also present in periphereral organs, and blood levels of A-beta correlate with cerebral amyloid burden and cognitive decline, raising the possibility that peripherally produced a-beta may contribute to the disease.

Testing that hypothesis has been difficult, said study author John Mamo of Curtin University in Bentley, Australia, since the brain also produces A-beta – and distinguishing protein from the two sources is challenging.

“While further studies are now needed, this finding shows the abundance of these toxic protein deposits in the blood could potentially be addressed through a person’s diet and some drugs that could specifically target lipoprotein amyloid, therefore reducing their risk or slowing the progression of Alzheimer’s disease,” says Mamo.

In the current study, the authors surmounted that challenge by developing a mouse that produces human a-beta only in liver cells. They showed that the protein was carried in the blood by triglyceride-rich lipoproteins, just as it is in humans, and passed from the periphery into the brain.

They found that mice developed neurodegeneration and brain atrophy, which was accompanied by neurovascular inflammation and dysfunction of cerebral capillaries, both commonly observed with Alzheimer’s disease. Affected mice performed poorly on a learning test that depends on function of the hippocampus, the brain structure that is essential for the formation of new memories.

The findings from this study indicate that peripherally derived A-beta has the ability to cause neurodegeneration and suggest that A-beta made in the liver is a potential contributor to human disease. If that contribution is significant, the findings may have major implications for understanding Alzheimer’s disease.

To date, most models of the disease have focused on brain overproduction of A-beta, which mimics the rare genetic cases of human Alzheimer’s.

But for the vast majority of AD cases, overproduction of A-beta in the brain is not thought to be central to the disease etiology. Instead, lifestyle factors may play a more important role, including a high-fat diet, which might accelerate liver production of A-beta.

The effects of peripheral A-beta on brain capillaries may be critical in the disease process, Mamo adds.

 

Dementia

Researchers find Alzheimer’s link in brain’s immune cells

The microglia breakthrough could help in the development of new therapies for patients

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The discovery of a new role for the brain’s immune cells could have implications for conditions including Alzheimer’s disease and stroke.

A research team has uncovered a vital but previously unknown role for microglia, immune cells that protect the brain from disease and injury, and help to regulate blood flow and maintain the brain’s critical blood vessels.

The researchers, from the University of Virginia School of Medicine, believe the findings could prove important in cognitive decline, dementia and stroke, among other conditions linked to diseases of the brain’s small vessels. 

“Precise blood vessel function is critical to accommodate the extreme energy demands of the brain for normal brain function,” said UVA’s Ukpong B. Eyo, of UVA’s Department of Neuroscience, the UVA Brain Institute and UVA’s Center for Brain Immunology and Glia (BIG). 

“These findings suggest previously unknown roles for these brain cells in the proper maintenance of blood delivery to the brain and provide novel opportunities to intervene in contexts where blood perfusion to the brain is impaired.”

The researchers believe their new findings could have significant implications for diseases that affect the small vessels of the brain. These conditions are thought to contribute to stroke, Alzheimer’s, loss of balance and mental decline, among other serious health problems.

“We are currently expanding this research into an Alzheimer’s disease context in rodents to investigate whether the novel phenomenon is altered in mouse models of the disease and determine whether we could target the mechanisms we uncovered to improve known deficits in blood flow in such a mouse model of Alzheimer’s,” Eyo said. 

“Our hope is that these findings in the lab could translate into new therapies in the clinic that would improve outcomes for patients.”

Scientists have known that microglia play many important roles in the brain and that microglia also facilitate the formation of the brain’s complex network of blood vessels during development. In Alzheimer’s disease, for example, recent work suggests that the loss of the immune cells is thought to increase harmful plaque buildup in the brain.

Scientists have been unsure, however, what role microglia play in maintaining blood vessels in a normal, healthy brain. The new research reveals for the first time that the cells are critical support staff, tending the vessels and even regulating blood flow.

The UVA researchers identified microglia associating with the brain’s capillaries, determined what the immune cells do there and revealed what controls those interactions. Among the cells’ important responsibilities is helping to regulate the diameter of the capillaries and possibly restricting or increasing blood flow as needed.

“Researchers have been studying these cells in the living brain for over two decades but this is the first time we are able to get an idea of these mechanisms of microglia-blood vessel interaction,” said Eyo, an expert on microglia. 

“It’s an exciting time to be the first to make these findings here at UVA.”

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Dementia

Is this the cause of Alzheimer’s disease?

Australian scientists have identified the probable ‘blood-to-brain pathway’ that can lead to the neurodegenerative condition

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Groundbreaking new research has discovered a likely cause of Alzheimer’s disease, in a significant finding that offers potential new prevention and treatment opportunities. 

The study identified that a probable cause of Alzheimer’s disease was the leakage from blood into the brain of fat-carrying particles transporting toxic proteins.

Lead investigator Professor John Mamo said his collaborative group of Australian scientists had identified the probable ‘blood-to-brain pathway’ that can lead to Alzheimer’s disease, the most prevalent form of dementia globally.

“While we previously knew that the hallmark feature of people living with Alzheimer’s disease was the progressive accumulation of toxic protein deposits within the brain called beta-amyloid, researchers did not know where the amyloid originated from, or why it deposited in the brain,” said Professor Mamo, of the Curtin Health Innovation Research Institute (CHIRI).

“Our research shows that these toxic protein deposits that form in the brains of people living with Alzheimer’s disease most likely leak into the brain from fat carrying particles in blood, called lipoproteins.

“This ‘blood-to-brain pathway’ is significant because if we can manage the levels in blood of lipoprotein-amyloid and prevent their leakage into the brain, this opens up potential new treatments to prevent Alzheimer’s disease and slow memory loss.”

Building on previous award-winning research that showed beta-amyloid is made outside the brain with lipoproteins, Professor Mamo’s team tested the pioneering ‘blood-to-brain pathway’ by genetically engineering mouse models to produce human amyloid-only liver that make lipoproteins.

“As we predicted, the study found that mouse models producing lipoprotein-amyloid in the liver suffered inflammation in the brain, accelerated brain cell death and memory loss,” Professor Mamo said.

“While further studies are now needed, this finding shows the abundance of these toxic protein deposits in the blood could potentially be addressed through a person’s diet and some drugs that could specifically target lipoprotein amyloid, therefore reducing their risk or slowing the progression of Alzheimer’s disease.”

Alzheimer’s WA Chairman Adjunct Professor Warren Harding said the findings may have a significant global impact for the millions of people living with Alzheimer’s disease.

“Having universities like Curtin working with the pharmaceutical industry is important if we are to tackle this devastating disease,” Mr Harding said.

“In Australia, approximately 250 people are diagnosed with dementia daily, adding to the staggering half a million Australians who are already living with dementia. 

“Without significant medical advances like the breakthrough Professor Mamo’s team has made, it is estimated that the number of Australians living with dementia will exceed one million by 2058. This has a significant impact on families, carers and communities.”

Professor Mamo and his research team’s previous research in this area was awarded the NHMRC-Marshall and Warren Award for the most innovative and potentially transformative research.

Currently, the team is conducting a clinical trial, the Probucol in Alzheimer’s-clinical trial, which is based on previous findings that a historic cardiovascular agent lowers lipoprotein-amyloid production and supports cognitive performance in mice. The mouse models used for this research were developed together with Ozgene.

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Dementia

Alzheimer’s could be detected before symptoms appear

People at a higher genetic risk may show differences in brain structure and in cognitive test scores

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Healthy people with a higher genetic risk of Alzheimer’s disease may show differences in brain structure and in cognitive test scores relating to reasoning and attention, a new study has revealed.

The research suggests that, although the association between these differences in people with a higher genetic risk of Alzheimer’s disease were small, signs of the neurodegenerative disease may be detectable before significant symptoms are obvious.

The study, from the University of Glasgow, is the largest study to date investigating the genetic risk for late-onset Alzheimer’s disease and non-demented structural brain MRI and cognition phenotypes.

Its findings have been hailed as a potential “real game changer” by the Alzheimer’s Society.

Alzheimer’s disease (AD) affects several brain regions, but among the earliest includes the hippocampus, which is vital for processing memory and learning.

Genetic factors are known to play a role in developing AD dementia, and researchers can use polygenic risk scoring – a method used to estimate an individual’s genetic risk of developing a particular disease, such as AD.

In this study, the researchers calculated a polygenic genetic risk score based on a large number of mutations for 32,790 generally-healthy adults without dementia from the UK Biobank, a large-scale biomedical database and research resource, to see if their lifetime genetic risk of AD was associated with average differences in brain structure and cognitive performance.

Rachana Tank, a lead author on the study, said: “Our findings are novel because they show the effects of genetic risk may, to a certain extent, be apparent long before a clinical dementia diagnosis. Although we cannot say for certain that these differences are early signs of dementia per se, it is important that we do further research in this area.

Dr Donald Lyall, from the University’s Institute of Health and Wellbeing, said: “These findings could lead to a better, more meaningfully informative way of gauging Alzheimer’s disease risk than current methods of inquiring about a family history of dementia, as being able to identify individuals at risk of worse cognitive abilities and potentially accelerated decline could greatly improve diagnosis and treatment options in future.”

Fiona Carragher, director of research and influencing at Alzheimer’s Society, said: “If we can accurately identify people at risk of developing Alzheimer’s disease later in life, it could be a real gamechanger.

“Early detection of those at a higher risk has the potential to pave the way for new treatments in the future and help researchers understand what causes diseases like Alzheimer’s to develop.

“The scale of this study is significant. It adds further evidence to the theory that some brain changes associated with Alzheimer’s disease can start many years before symptoms such as memory loss.

“However, it only looked at people from a white European background – we need to better understand whether there are associations between different genetic risk factors and changes in the brain in people from other ethnic communities.

“Research will beat dementia, but we need more funding. The Government must honour their commitment to double dementia research funding to provide hope for future generations. We owe to the 850,000 people in the UK currently living with dementia.”

 

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