Green tea and red wine extracts interrupt Alzheimer’s disease pathway in cells

Natural chemicals found in green tea and red wine may disrupt a key step of the Alzheimer’s disease pathway, according to new research from the University of Leeds.

In early-stage laboratory experiments, the researchers identified the process which allows harmful clumps of protein to latch on to brain cells, causing them to die. They were able to interrupt this pathway using the purified extracts of EGCG from green tea and resveratrol from red wine.

The findings, published in the Journal of Biological Chemistry, offer potential new targets for developing drugs to treat Alzheimer’s disease, which affects some 800,000 people in the UK alone, and for which there is currently no cure.

"This is an important step in increasing our understanding of the cause and progression of Alzheimer’s disease," says lead researcher Professor Nigel Hooper of the University’s Faculty of Biological Sciences. "It’s a misconception that Alzheimer’s is a natural part of ageing; it’s a disease that we believe can ultimately be cured through finding new opportunities for drug targets like this."

Alzheimer’s disease is characterised by a distinct build-up of amyloid protein in the brain, which clumps together to form toxic, sticky balls of varying shapes. These amyloid balls latch on to the surface of nerve cells in the brain by attaching to proteins on the cell surface called prions, causing the nerve cells to malfunction and eventually die.

"We wanted to investigate whether the precise shape of the amyloid balls is essential for them to attach to the prion receptors, like the way a baseball fits snugly into its glove," says co-author Dr Jo Rushworth. "And if so, we wanted to see if we could prevent the amyloid balls binding to prion by altering their shape, as this would stop the cells from dying."

The team formed amyloid balls in a test tube and added them to human and animal brain cells. Professor Hooper said: “When we added the extracts from red wine and green tea, which recent research has shown to re-shape amyloid proteins, the amyloid balls no longer harmed the nerve cells. We saw that this was because their shape was distorted, so they could no longer bind to prion and disrupt cell function.

"We also showed, for the first time, that when amyloid balls stick to prion, it triggers the production of even more amyloid, in a deadly vicious cycle," he added.

Professor Hooper says that the team’s next steps are to understand exactly how the amyloid-prion interaction kills off neurons.

"I’m certain that this will increase our understanding of Alzheimer’s disease even further, with the potential to reveal yet more drug targets," he said.

Dr Simon Ridley, Head of Research at Alzheimer’s Research UK, the UK’s leading dementia research charity, which part-funded the study, said: “Understanding the causes of Alzheimer’s is vital if we are to find a way of stopping the disease in its tracks. While these early-stage results should not be a signal for people to stock up on green tea and red wine, they could provide an important new lead in the search for new and effective treatments. With half a million people affected by Alzheimer’s in the UK, we urgently need treatments that can halt the disease – that means it’s crucial to invest in research to take results like these from the lab bench to the clinic.”

The zebrafish revealed a central regulator for the development of the brain histamine system

Research has shown that mutations in the psen1 gene are common in the familial forms of Alzheimer’s disease, and the Presenilin-1 protein that the gene encodes is known to be involved in the cleavage of the amyloid precursor protein. In Alzheimer’s disease the amyloid precursor protein is not cleaved the normal way, and the protein accumulates in the brain damaging neuronal tracts and neurons. It is still unknown if the psen1 gene is involved in the etiology of Alzheimer’s disease via another mechanism.

Professor Pertti Panula’s research team at the University of Helsinki has elucidated the role of psen1 gene in the development of the neuronal histamine system and its modulation. Histamine is one of the neurotransmitters, which all are essential for cognitive functions, which in turn are impaired in Alzheimer’s disease. The histamine system is altered during the progression of Alzheimer’s disease.

In the study the zebrafish was used as a model organism. The rapidly developing zebrafish is suitable as a model organism, as its transparency allows researchers to study the development and function of vital organs. To study the function of psen1 gene, zebrafish that did not produce functional Presenilin-1 protein were generated. Despite the fact that the fish lacked functional Presenilin-1 they were viable and developed until adulthood.

The lack of Presenilin-1 protein induced a change in the behavior of the larval zebrafish, they did not as normal fish react to fast changes in the light intensity. “Based on previous research we know that this change in behavior is associated with lack of histamine in the brain”, Panula explains.

In adulthood the motor behavior of the mutant zebrafish differed from the normal fish: the fish swam by the edges of the arena that was available and avoided the inner part. Previous studies from the group have shown that this behavioral alteration also is due to changes in the histamine system.

The researchers found that larval fish lacking Presenilin-1 protein had significantly fewer histamine neurons; in adulthood the histamine neuron number was significantly increased in these fish when compared with normal fish.

"These results reveal that the psen1 gene is a central regulator of the development of the histamine neurons and that the mutation can cause a persistent lifelong change in the neuronal histamine system. This is a very interesting finding", Panula states.

One interesting remaining question is from where the new histamine neurons arise in the brains of adult zebrafish. Are they newly differentiated stem cells or do other cells become histamine neurons? The answer is not known, but based on these results it is advisable to elucidate the role of Presenilin-1 protein in differentiation of stem cells also in the brains of mammals. “Mammals have stem cells in the hypothalamus, in the same area where the histamine neurons are located in all studied vertebrates”, Panula comments.

Panula empathizes that the published study does not tell about an Alzheimer’s disease mechanism in humans. The new knowledge on the function of psen1 gene and the development of the brain histamine system provided by the study is one step forward to understanding the etiology of the disease.

"We perform basic research on molecular level, from where it is a long way to treatment of human diseases. This type of research provides the findings on which the treatments are finally based", Panula says.

Journal of Neuroscience published the study that was conducted at University of Helsinki Neuroscience center, and Institute of Biomedicine.

(Image: Charles Badland, Florida State University)

Vitamin D, omega-3 may help clear amyloid plaques found in Alzheimer’s

A team of academic researchers has pinpointed how vitamin D3 and omega-3 fatty acids may enhance the immune system’s ability to clear the brain of amyloid plaques, one of the hallmarks of Alzheimer’s disease.

In a small pilot study published in the Feb. 5 issue of the Journal of Alzheimer’s Disease, the scientists identified key genes and signaling networks regulated by vitamin D3 and the omega-3 fatty acid DHA (docosahexaenoic acid) that may help control inflammation and improve plaque clearance.

Previous laboratory work by the team helped clarify key mechanisms involved in helping vitamin D3 clear amyloid-beta, the abnormal protein found in the plaque. The new study extends the previous findings with vitamin D3 and highlights the role of omega-3 DHA.

"Our new study sheds further light on a possible role for nutritional substances such as vitamin D3 and omega-3 in boosting immunity to help fight Alzheimer’s," said study author Dr. Milan Fiala, a researcher at the David Geffen School of Medicine at UCLA.

Study Confirms No Transmission of Alzheimer’s Proteins Between Humans

Mounting evidence demonstrates that the pathological proteins linked to the onset and progression of neurodegenerative disorders are capable of spreading from cell-to-cell within the brains of affected individuals and thereby “spread” disease from one interconnected brain region to another. A new study found no evidence to support concerns that these abnormal disease proteins are “infectious” or transmitted from animals to humans or from one person to another. The study by researchers from the Perelman School of Medicine at the University of Pennsylvania, in conjunction with experts from the U.S. Centers for Disease Control and the Department of Health and Human Services, appears online in JAMA Neurology.

Cell-to-cell transmission is a potentially common pathway for disease spreading and progression in diseases like Alzheimer’s (AD) and Parkinson’s (PD) disease as well as frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS) and other related disorders. It appears that misfolded proteins spread from one cell to another and that the affected neurons become dysfunctional, while these toxic proteins go on to damage other regions of the brain over time.

"By interrogating an existing database with information on a cohort of well-characterized patients, we were able to determine that there is no evidence suggesting the pathology of Alzheimer’s or Parkinson’s can transmit between humans,"  said senior author John Q. Trojanowski, MD, PhD, professor of Pathology and Laboratory Medicine and co-director of the Penn Center for Neurodegenerative Disease Research. "We can now redouble efforts to find treatments, via immunotherapies or other approaches to stop the spreading of these toxic proteins between cells."

In order to verify whether such proteins could potentially be carried from person to person, the team of researchers analyzed data from an existing cohort of patients who had received human growth hormone (hGH) from cadaveric pituitary glands via a national program, as a beneficial treatment for stunted growth, before synthetic hGH was available. Nearly 7,700 patients were treated with cadaver-derived hGH (c-hGH) in the US between 1963 and 1985. In the mid-1980s, more than 200 patients worldwide who had received c-hGH inadvertently contaminated with prion proteins from affected donor pituitary tissue went on to develop an acquired form of Creutzfeldt-Jakob disease (CJD), a rare, degenerative, invariably fatal brain disorder caused by pathological prion proteins that also are the cause of Mad Cow disease. Since then, the cohort has been followed to track any additional cases of CJD, with extensive medical histories for patients over the 30+ years since the c-hGH therapy was stopped after the link to CJD was discovered in 1985.

Damaged Blood Vessels Loaded with Amyloid Worsen Cognitive Impairment in Alzheimer’s Disease

A team of researchers at Weill Cornell Medical College has discovered that amyloid peptides are harmful to the blood vessels that supply the brain with blood in Alzheimer’s disease — thus accelerating cognitive decline by limiting oxygen-rich blood and nutrients. In their animal studies, the investigators reveal how amyloid-ß accumulates in blood vessels and how such accumulation and damage might be ultimately prevented.

Their study, published in the Feb. 4 online edition of the Proceedings of the National Academy of Sciences (PNAS), is the first to identify the role that the innate immunity receptor CD36 plays in damaging cerebral blood vessels and promoting the accumulation of amyloid deposits in these vessels, a condition known as cerebral amyloid angiopathy (CAA).

Importantly, the study provides the rational bases for targeting CD36 to slow or reverse some of the cognitive deficits in Alzheimer’s disease by preventing CAA.

"Our findings strongly suggest that amyloid, in addition to damaging neurons, also threatens the cerebral blood supply and increases the brain’s susceptibility to damage through oxygen deprivation," says the study’s senior investigator, Dr. Costantino Iadecola, the Anne Parrish Titzell Professor of Neurology at Weill Cornell Medical College and director of the Brain and Mind Research Institute at Weill Cornell Medical College and NewYork-Presbyterian Hospital. "If we can stop accumulation of amyloid in these blood vessels, we might be able to significantly improve cognitive function in Alzheimer’s disease patients. Furthermore, we might be able to improve the effectiveness of amyloid immunotherapy, which is in clinical trials but has been hampered by the accumulation of amyloid in cerebral blood vessels."

Mounting scientific evidence shows that changes in the structure and function of cerebral blood vessels contribute to brain dysfunction underlying Alzheimer’s disease, but no one has truly understood how this happens until now.

Treatment to prevent Alzheimer’s disease moves a step closer

A new drug to prevent the early stages of Alzheimer’s disease could enter clinical trials in a few years’ time according to scientists.

Alzheimer’s is the most common type of dementia, which currently affects 820,000 people in the UK, with numbers expected to more than double by 2050. One in three people over 65 will die with dementia.

The disease begins when a protein called amyloid-β (Aβ) starts to clump together in senile plaques in the brain, damaging nerve cells and leading to memory loss and confusion.

Professor David Allsop and Dr Mark Taylor at Lancaster University have successfully created a new drug which can reduce the number of senile plaques by a third, as well as more than doubling the number of new nerve cells in a particular region of the brain associated with memory.  It also markedly reduced the amount of brain inflammation and oxidative damage associated with the disease.

The drug was tested on transgenic mice containing two mutant human genes linked to inherited forms of Alzheimer’s, so that they would develop some of the changes associated with the illness. The drug is designed to cross the blood-brain barrier and prevent the Aβ molecules from sticking together to form plaques.

Professor Allsop, who led the research and was the first scientist to isolate senile plaques from human brain, said: “When we got the test results back, we were highly encouraged. The amount of plaque in the brain had been reduced by a third and this could be improved if we gave a larger dose of the drug, because at this stage, we don’t know what the optimal dose is.”

The drug needs to be tested for safety before it can enter human trials, but, if it passes this hurdle, the aim would be to give the drug to people with mild symptoms of memory loss before they develop the illness.

“Many people who are mildly forgetful may go on to develop the disease because these senile plaques start forming years before any symptoms manifest themselves. The ultimate aim is to give the drug at that stage to stop any more damage to the brain, before it’s too late.”

Support for the research was given by Alzheimer’s Research UK, and the results are published in the open access journal PLOS ONE.