Scientists link 'hunger hormone' to memory in Alzheimer's study

September 3, 2019

Science Daily/University of Texas at Dallas

Scientists at The University of Texas at Dallas have found evidence suggesting that resistance to the "hunger hormone" ghrelin in the brain is linked to the cognitive impairments and memory loss associated with Alzheimer's disease (AD).

The findings, based on observations of postmortem brain-tissue samples from Alzheimer's patients and on experiments with a mouse model of AD, also suggest a possible treatment strategy for the incurable neurodegenerative disorder that affects about 5.8 million older adults in the United States.

The research was published Aug. 14 as the cover article in the journal Science Translational Medicine.

"This is a proof-of-concept study, but we are very encouraged by the results," said Dr. Heng Du, associate professor of biological sciences at UT Dallas and corresponding author of the study.

Produced in the stomach, ghrelin sends signals to the brain that regulate energy balance and body weight. Often called the hunger hormone, it plays a role in appetite and meal initiation. But ghrelin also has been implicated in learning and memory.

The hippocampus region of the brain -- crucial to learning, memory and emotions -- is one of the first to suffer cell death and damage in Alzheimer's disease due to a toxic buildup of protein fragments called amyloid beta.

In a healthy hippocampus, ghrelin binds with proteins called ghrelin receptors, which combine with similarly activated receptors for the neurotransmitter dopamine. The two receptors then form a protein complex that helps maintain communication between brain cells and, ultimately, memory.

In the new study, Du and his colleagues found that amyloid beta binds to ghrelin receptors in the hippocampus, blocking their ability to combine with dopamine receptors.

"Our hypothesis is that this dissociation between ghrelin and dopamine receptors may be what is affecting cognition in Alzheimer's patients," Du said. "As the brain loses the function of ghrelin receptors due to amyloid beta, the body tries to compensate by increasing the production of ghrelin and the number of ghrelin receptors. But the amyloid prevents the receptors from functioning."

Du likened the condition to insulin resistance found in individuals with type 2 diabetes. In that disease, insulin receptors malfunction.

"To compensate, patients in the early stages of type 2 diabetes produce more insulin to bind insulin receptors," Du said. "But they become insulin-resistant. No matter how much insulin your body produces, the insulin receptors are unable to activate the downstream biochemical reactions needed to transport glucose from blood into cells.

"Similarly, based on our findings, Alzheimer's might be linked to ghrelin resistance."

Du said the new findings help explain why a recent clinical trial of a compound called MK0677 -- designed to activate ghrelin receptors in the brain -- proved unable to slow the progression of Alzheimer's.

To test a different approach in their mouse model of AD, Du's team gave the mice MK0677 and another compound -- SKF81297 to activate dopamine receptors -- at the same time.

"When we gave these compounds simultaneously, we saw improved cognition and memory in the AD mice, and lesions in the hippocampus were reduced," Du said. "Activating both receptors at the same time was key; it restored the receptors' ability to form complexes. When this happens, we suspect the ghrelin receptor becomes protected and can no longer bind to amyloid beta.

"More research is needed, but targeting this mechanism might prove therapeutically useful."

Du, who has filed for a patent on the approach, said the team's findings suggest that Alzheimer's might be more than just a brain disease.

"As we age, we tend to experience changes in metabolism. These affect the heart and the gastrointestinal system, but maybe they also are affecting the brain by altering the ghrelin receptor," he said. "We know that even in the absence of dementia, many older people have memory problems, and this could be related to the dissociation between the receptors in the brain, even without the presence of amyloid.

"I'm starting to think of Alzheimer's as a systemic disorder, and that we should pay more attention to the metabolic and hormonal path of the disease."

https://www.sciencedaily.com/releases/2019/09/190903173401.htm

Diet's effect on gut bacteria could play role in reducing Alzheimer's risk

September 3, 2019

Science Daily/Wake Forest Baptist Medical Center

Could following a certain type of diet affect the gut microbiome -- the good and bad bacteria that live in the gastrointestinal tract -- in ways that decrease the risk of Alzheimer's disease?

According to researchers at Wake Forest School of Medicine, that is a fair possibility.

In a small pilot study, the researchers identified several distinct gut microbiome signatures -- the chemicals produced by bacteria -- in study participants with mild cognitive impairment (MCI) but not in their counterparts with normal cognition, and found that these bacterial signatures correlated with higher levels of markers of Alzheimer's disease in the cerebrospinal fluid of the participants with MCI.

Through cross-group dietary intervention, the study also showed that a modified Mediterranean-ketogenic diet produced changes in the gut microbiome and its metabolites that correlated with reduced levels of Alzheimer's markers in the members of both study groups.

The study appears in the current issue of EBioMedicine, a journal published by The Lancet.

"The relationship of the gut microbiome and diet to neurodegenerative diseases has recently received considerable attention, and this study suggests that Alzheimer's disease is associated with specific changes in gut bacteria and that a type of ketogenic Mediterranean diet can affect the microbiome in ways that could impact the development od dementia," said Hariom Yadav, Ph.D., assistant professor of molecular medicine at Wake Forest School of Medicine, who co-authored the study with Suzanne Craft, Ph.D., professor gerontology and geriatric medicine at the medical school and director of Wake Forest Baptist Health's Alzheimer's Disease Research Center.

The randomized, double-blind, single-site study involved 17 older adults, 11 with diagnosed MCI and six with normal cognition. These participants were randomly assigned to follow either the low-carbohydrate modified Mediterranean-ketogenic diet or a low-fat, higher carbohydrate diet for six weeks then, after a six-week "washout" period, to switch to the other diet. Gut microbiome, fecal short-chain fatty acids and markers of Alzheimer's, including amyloid and tau proteins, in cerebrospinal fluid were measured before and after each dieting period.

The study's limitations include the subject group's size, which also accounts for the lack of diversity in terms of gender, ethnicity and age.

"Our findings provide important information that future interventional and clinical studies can be based on," Yadav said. "Determining the specific role these gut microbiome signatures have in the progression of Alzheimer's disease could lead to novel nutritional and therapeutic approaches that would be effective against the disease."

https://www.sciencedaily.com/releases/2019/09/190903120514.htm

Creation of new brain cells plays an underappreciated role in Alzheimer's disease

August 30, 2019

Science Daily/University of Chicago

Researchers show how in genetic forms of Alzheimer's, a process called neurogenesis, or the creation of new brain cells, can be disrupted by the brain's own immune cells.

Much of the research on the underlying causes of Alzheimer's disease focuses on amyloid beta (Aß), a protein that accumulates in the brain as the disease progresses. Excess Aß proteins form clumps or "plaques" that disrupt communication between brain cells and trigger inflammation, eventually leading to widespread loss of neurons and brain tissue.

Aß plaques will continue to be a major focus for Alzheimer's researchers. However, new work by neuroscientists at the University of Chicago looks at another process that plays an underappreciated role in the progression of the disease.

In a new study published in the Journal of Neuroscience, Sangram Sisodia, PhD, the Thomas Reynolds Sr. Family Professor of Neurosciences at UChicago, and his colleagues show how in genetic forms of Alzheimer's, a process called neurogenesis, or the creation of new brain cells, can be disrupted by the brain's own immune cells.

Some types of early onset, hereditary Alzheimer's are caused by mutations in two genes called presenilin 1 (PS1) and presenilin 2 (PS2). Previous research has shown that when healthy mice are placed into an "enriched" environment where they can exercise, play and interact with each other, they have a huge increase in new brain cells being created in the hippocampus, part of the brain that is important for memory. But when mice carrying mutations to PS1 and PS2 are placed in an enriched environment, they don't show the same increase in new brain cells. They also start to show signs of anxiety, a symptom often reported by people with early onset Alzheimer's.

This led Sisodia to think that something besides genetics had a role to play. He suspected that the process of neurogenesis in mice both with and without Alzheimer's mutations could also be influenced by other cells that interact with the newly forming brain cells.

Focus on the microglia

The researchers focused on microglia, a kind of immune cell in the brain that usually repairs synapses, destroys dying cells and clears out excess Aß proteins. When the researchers gave the mice a drug that causes microglial cells to die, neurogenesis returned to normal. The mice with presenilin mutations were then placed into an enriched environment and they were fine; they didn't show any memory deficits or signs of anxiety, and they were creating the normal, expected number of new neurons.

"It's the most astounding result to me," Sisodia said. "Once you wipe out the microglia, all these deficits that you see in these mice with the mutations are completely restored. You get rid of one cell type, and everything is back to normal."

Sisodia thinks the microglia could be overplaying their immune system role in this case. Alzheimer's disease normally causes inflammation in the microglia, so when they encounter newly formed brain cells with presenilin mutations they may overreact and kill them off prematurely. He feels that this discovery about the microglia's role opens another important avenue toward understanding the biology of Alzheimer's disease.

"I've been studying amyloid for 30 years, but there's something else going on here, and the role of neurogenesis is really underappreciated," he said. "This is another way to understand the biology of these genes that we know significantly affect the progression of disease and loss of memory."

https://www.sciencedaily.com/releases/2019/08/190830112832.htm

A protective factor against Alzheimer's disease?

August 29, 2019

Science Daily/DZNE - German Center for Neurodegenerative Diseases

Researchers at the German Center for Neurodegenerative Diseases (DZNE) and the Institute for Stroke and Dementia Research (ISD) at the University Hospital of the Ludwig-Maximilians-Universität (LMU) in Munich have found that a protein called TREM2 could positively influence the course of Alzheimer's disease. When TREM2 is present in the cerebrospinal fluid at higher concentrations, patients at any stage of the disease have a better prognosis. This observation provides a starting point for the development of new therapeutic strategies. The study was led by Prof. Christian Haass (DZNE) and Prof. Michael Ewers (ISD, LMU) and is published in the journal Science Translational Medicine.

In the brain, TREM2 is exclusively produced by microglia, the immune cells of the brain. These cells patrol the brain and clear it from cellular waste products and debris to keep it healthy. In previous studies on mice, Haass and his colleagues demonstrated that TREM2 activates microglia to enclose and selectively destroy toxic protein aggregates typical for Alzheimer's disease. "These observations indicate that TREM2 can protect the brain from the degenerative effects of the disease -- at least in animal models," said Haass.

But what about patients with Alzheimer's disease? Does TREM2 protect the human brain as well? To answer these questions, Haass, Ewers, and their colleagues correlated the concentration of TREM2 in the cerebrospinal fluid of Alzheimer patients with their respective disease progression over several years. To this end, they used data of 385 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a large clinical dataset containing records and samples from patients and healthy seniors taken at regular checkups over many years. The study thus allows to establish associations between certain biochemical changes and disease progression.

Indeed, Haass and Ewers found that high levels of TREM2 improved the prognosis of subjects at all stages of the disease. Their memory remained more stable and the degradation of the hippocampus, a brain region responsible for learning and recollection, was less pronounced. "Our findings are clinically relevant because we found that higher levels of TREM2 were associated also with a reduced rate of the development of full blown dementia over a time period up to 11 years," explained Ewers. "Microglia activation is a double-edged sword, entailing both protective effects and neurotoxic inflammation. TREM2 signaling may play a key role in the regulation of the brain's protective immune response."

The concentration of TREM2 in the cerebrospinal fluid usually increases at early stages of the disease, when the first symptoms appear. "TREM2 production is a response to brain damage that has already occurred," said Haass. "It stimulates the microglia to protect the brain. However, this protection does not seem to be sufficient in patients with Alzheimer's disease." This is where Haass and his colleagues see an option for new therapeutic strategies. "We are currently developing a therapeutic antibody that stimulates the TREM2 function and thus improves its protective function," said Haass.

https://www.sciencedaily.com/releases/2019/08/190829150718.htm

Could marriage stave off dementia?

August 28, 2019

Science Daily/Michigan State University

Dementia and marital status could be linked, according to a new Michigan State University study that found married people are less likely to experience dementia as they age.

On the other hand, divorcees are about twice as likely as married people to develop dementia, the study indicated, with divorced men showing a greater disadvantage than divorced women.

In one of the first studies of its kind, Hui Liu, professor of sociology, and colleagues analyzed four groups of unmarried individuals: divorced or separated; widowed; never married; and cohabiters. Among them, the divorced had the highest risk of dementia.

The study, published in The Journals of Gerontology: Series B, comes at a time when 5.8 million people in the U.S. are living with Alzheimer's disease and related dementias, costing $290 billion, according to the Alzheimer's Association. It's a serious public health concern, Liu said.

"This research is important because the number of unmarried older adults in the United States continues to grow, as people live longer and their marital histories become more complex," Liu said. "Marital status is an important but overlooked social risk/protective factor for dementia."

Liu and her follow researchers analyzed nationally representative data from the Health and Retirement Study, from 2000 to 2014. The sample included more than 15,000 respondents ages 52 and older in 2000, measuring their cognitive function every two years, in person or via telephone.

The researchers also found differing economic resources only partly account for higher dementia risk among divorced, widowed and never-married respondents, but couldn't account for higher risk in cohabiters. In addition, health-related factors, such as behaviors and chronic conditions, slightly influenced risk among the divorced and married, but didn't seem to affect other marital statuses.

"These findings will be helpful for health policy makers and practitioners who seek to better identify vulnerable populations and to design effective intervention strategies to reduce dementia risk," Liu said.

https://www.sciencedaily.com/releases/2019/08/190828100542.htm

Memory loss, dementia an understudied yet widespread phenomenon among Chinese Americans

August 26, 2019

Science Daily/Rutgers University

First of their kind studies reveal the impact of immigration, gender, psychological distress, education, social engagement, and oral health on Chinese Americans' cognitive function.

The U.S. Chinese population is growing -- and graying -- rapidly. From 2000 to 2010, the Chinese American population aged 65 and over grew at a rate four times higher than the overall U.S. older adult population. As of 2016, 14% of the approximately four million Chinese Americans were aged 65 and older. As this population ages, they are increasingly susceptible to memory loss and lacking the necessary supports for healthy aging, according to four new Rutgers studies published in the Journal of the American Geriatrics Society.

The studies are the first to extensively study memory loss and dementia in the context of immigration, gender, psychological distress, education, social engagement, and oral health among older Chinese Americans. The papers explore the risk factors and offer recommendations for healthcare providers to overcome the linguistic, cultural, and socioeconomic barriers facing this vulnerable population.

"Research has found that as many as 34% of American adults aged 60 and older are cognitively impaired," said XinQi Dong, director of Rutgers University's Institute for Health, Health Care Policy and Aging Research. " Further, more than one in four people aged 65 and older will be diagnosed with dementia in their lifetime. Although these facts are known to apply to the general American population, there is little information about Alzheimer's disease and related dementias or the contributing factors among Asian Americans."

For the studies, researchers administered multiple cognitive function tests to 2,713 Chinese Americans aged 60 and older. They measured the effects of immigration and gender, psychological distress, education level and social engagement, and oral health on the three domains of cognitive function -- global cognition, episodic memory, and working memory.

Key findings:

·      Older Chinese American women experience higher rates of cognitive impairment.

·      Depression, chronic conditions, and disability are associated with cognitive decline.

·      Lower education levels increase the risk of cognitive impairment. A one-year increase in education decreases the risk by 25%.

·      Difficulties performing functional and instrumental activities of daily living are predictive of the risk of developing cognitive impairment.

·      Higher levels of perceived stress are associated with poorer episodic memory, perceptual speed, and working memory in older Chinese American adults

·      Stress negatively affects the brain and cognitive functioning throughout life.

·      Older Chinese Americans who face increased stressors from linguistic and cultural barriers have poorer cognitive functioning and faster cognitive decline.

·      41.5% of Asian Americans reported not receiving annual oral health examinations, which is linked to decreased quality of life, depression, hypertension, poor cognition, and cognitive decline.

"Chinese older adults are confronting significant life challenges and health disparities due to multiple social, structural, cultural and linguistic barriers," said Dong. "A thorough understanding of Chinese Americans' cognitive risk factors is necessary to guide the development of policy and interventions to delay the onset of memory loss," Dong continued.

"Researchers, social workers, and policymakers must collaborate to reduce health disparities and expand access to culturally-sensitive care for older Chinese American adults," he continued. "Developing programs and interventions that reduce stress, increase activity engagement, and improve quality of care, is necessary to limit memory loss among the aging U.S. Chinese population."

The studies can be found in the August 2019 Journal of the American Geriatrics Society, "Special Issue: Transforming Asian Health Equity: Findings from the PINE/PIETY Study": https://onlinelibrary.wiley.com/toc/15325415/2019/67/S3

https://www.sciencedaily.com/releases/2019/08/190826121927.htm

Heart attack patients with mild cognitive impairment get fewer treatments

August 23, 2019

Science Daily/Michigan Medicine - University of Michigan

A new study finds people who have mild cognitive impairment (MCI), which lies on the continuum of cognitive decline between normal cognition and dementia, are less likely to receive proven heart attack treatment in the hospital.

Researchers found no evidence that those with MCI would derive less benefit from evidence-based treatment that's offered to their cognitively normal peers who have heart attacks, says lead author Deborah Levine, M.D., MPH.

"Patients should get the treatments they would want if they were properly informed," says Levine, an associate professor of internal medicine and neurology at Michigan Medicine, the academic medical center of the University of Michigan.

Some people with thinking, memory and language problems have MCI. Unlike dementia, which severely interferes with daily functioning and worsens over time, MCI does not severely interfere with daily functioning and might not worsen over time. Although people with MCI have an increased risk of developing dementia, it's not an inevitable next step, Levine says.

"While some may progress to dementia, many will persist in having MCI, and a few will actually improve and revert to normal cognition," says Levine, also a member of the University of Michigan Institute for Healthcare Policy and Innovation. "Many older adults with MCI live years with good quality of life, and so face common health risks of aging like heart attack and stroke.

"Clinicians, patients and families might be overestimating the risk of dementia after a mild cognitive impairment diagnosis even without realizing it. These older adults with MCI should still receive evidence-based treatments when indicated."

The research, published in the Journal of General Internal Medicine, found pre-existing MCI was associated with significantly lower use of guideline-concordant care after a heart attack, whether catheter-based or open surgery. The study measured 609 adults ages 65 and older who were hospitalized for a heart attack between 2000 and 2011.

Levine notes both cardiac catheterization (35% less likely in patients with pre-existing MCI) and coronary revascularization (45% less likely in patients with pre-existing MCI) have been shown to be highly effective at reducing deaths and improving physical functioning after heart attack in multiple large clinical trials.

'A timely issue'

Physicians must weigh the competing risks of all health problems that increase with age, Levine says, including heart disease and cognitive decline. Many families are dealing with both concerns at once in their older loved ones.

"This is a timely issue because as the population ages, the number of seniors 85 years old and older has become the fastest-growing segment of the U.S. population," Levine says. "Seniors 85 and older are most likely to have MCI, and their incidence of heart attack has surged."

However, cardiovascular disease, including heart attack and stroke, is still the leading cause of death and serious morbidity in older adults, whether they have MCI or normal cognitive functioning.

Up to 1 in 5 adults ages 65 and older has MCI, although many may be undiagnosed, Levine says. Since the Affordable Care Act mandated coverage of cognitive impairment assessments for Medicare beneficiaries, MCI diagnoses are expected to increase, she adds.

The need to question decision-making

Although much recent medical literature addresses overtreatment, Levine says this research shows undertreatment with high-value therapies can also be a problem.

Her team's ongoing research finds physicians might not be recommending invasive treatments as often after an older patient with some memory and thinking problems has a heart attack. She encourages clinicians to reflect on the influence of MCI in their decision-making.

"It's important for providers to consider whether they are recommending against treating a patient just because they have MCI," Levine says. "Physicians can think about offering treatments to all patients when clinically indicated."

Invasive treatments may not be indicated in those with advanced dementia or a limited life expectancy, she says, but MCI does not fall in that category.

This potential disconnect in provider recommendations provides an opportunity for patients and families to empower themselves by having conversations about the care they'd want if they become ill, she says. People with MCI can still participate in these types of discussions, and families don't need to wait until an event happens to start the conversation.

"In these discussions, patients and families often think about catastrophic illnesses where life support measures may be used, but heart attacks and stroke are much more common, and they're treatable," Levine says.

"Because dementia is so feared among older adults and their families, it's understandable and appropriate that it may weigh heavily on the decisions for all types of care, including heart attack care," adds co-author Kenneth Langa, M.D., Ph.D., a professor of internal medicine at Michigan Medicine and a member of the Institute for Healthcare Policy and Innovation. "Our study emphasizes the importance of differentiating between MCI and dementia and of educating patients, families and clinicians on the relative risks of further cognitive decline versus common cardiovascular conditions for people with MCI."

An ongoing effort

Levine and colleagues used data from the Health and Retirement Study, a nationally representative longitudinal study of older Americans that's based at U-M.

Heart attack, or acute myocardial infarction, was an appealing lens to research whether patients with MCI receive guideline-based treatment, Levine says. Heart attacks are acute, emergent medical problems that are common in seniors and have robust evidence of effective treatment, she adds.

Levine's team is also studying the effect of pre-existing MCI on treatment for acute ischemic stroke, and the reasons physician recommendations and patient preferences for effective treatment after stroke or heart attack might be different if the patient already has MCI.

"Studies like this are an important first step in raising awareness on MCI so that providers, like cardiologists, can make sure they offer the best therapies available during heart attacks," says senior author Brahmajee Nallamothu, M.D., MPH, an interventional cardiologist and professor of internal medicine at Michigan Medicine.

https://www.sciencedaily.com/releases/2019/08/190823182709.htm

Carriers of Alzheimer's genetic marker have greater difficulty harnessing past knowledge

August 22, 2019

Science Daily/Baycrest Centre for Geriatric Care

Adults carrying a gene associated with a higher risk of Alzheimer's disease had a harder time accessing recently acquired knowledge, even though they didn't show any symptoms of memory problems, according to findings published in a joint Baycrest-University of Oxford study.

Researchers found that older adults carrying a specific strain of the gene, apolipoprotein E4, otherwise known as APOE4, weren't able to tap into information they had just learned to assist them on a listening test.

These findings suggest greater difficulty for these individuals to access knowledge from their memory to guide their attention in ways that would have improved their performance, according to the study published in the journal Scientific Reports. This work could lead to the development of new ways to detect individuals at risk.

The research team worked with 60 research participants (aged 40 to 61) from the Oxford Biobank who had varying combinations of APOE genes -- which includes one group of individuals with a combination of APOE3/APOE4 genes, one group of individuals with a set of APOE4 genes and one group of individuals with a set of APOE3 genes. All research participants had normal hearing, scored within the normal range of cognitive assessments and completed a questionnaire about their memory.

Each research participant listened to 92 audio clips and they were told to pay attention to where the clip was coming from, whether it was presented in the left, right or both ears. After the clip was played, they were asked which side they heard the sound from and if they responded incorrectly, the sound was replayed. Participants had a one-hour break before hearing the 92 audio clips again, but this time they were asked whether there was an additional sound at the end of the clip and to press a button when they heard it. Each clip was placed twice. During the first play-through, the clip's location was replayed and during the second play-through, the additional tone was added.

The study found that no matter the APOE genotype, all older adults were able to learn the information and remember the location of the audio clip, but individuals with the APOE4 gene had greater difficulty in identifying the additional sound at the end of the clip.

"For some reason, people with the APOE4 gene were not able to take advantage of information they learned earlier, such as the expected location of the clip, to boost their performance," says Dr. Claude Alain, a senior author on the paper and senior scientist at Baycrest's Rotman Research Institute. "This study shows we have a test that is sensitive to capture problems or challenges faced by individuals with this gene, before their deficits are observed on a standard neuropsychological assessment."

This was an exciting study looking at healthy, middle-aged people who carry a gene that increases their risk of developing Alzheimer's disease by 15-fold, says Dr. Chris Butler, a senior author on the paper and an associate professor in clinical neurosciences at the University of Oxford.

"The research could lead to more sensitive methods of detecting Alzheimer's disease in its very earliest stages, the time at which treatments are most likely to be effective," says Dr. Butler. "I was delighted to carry out this work with researchers from Baycrest."

As next steps, researchers continue to explore how the brain's ability to process what is heard changes with neurodegenerative conditions, such as mild cognitive impairment.

https://www.sciencedaily.com/releases/2019/08/190822141908.htm

Insight into cells' 'self-eating' process could pave the way for new dementia treatments

August 21, 2019

Science Daily/University of Plymouth

Cells regularly go through a process called autophagy -- literally translated as 'self-eating' -- which helps to destroy bacteria and viruses after infection.

When it works, this process counteracts neurodegenerative conditions such as dementia and Huntington's Disease, by getting rid of unwanted proteins and their resultant harm to cells.

But when autophagy fails or defects occur, it can give rise to such conditions.

Now new research by the University of Plymouth has shed light on the mechanisms behind autophagy and how it progresses -- particularly relating to a process called liquid-liquid phase separation (LLPS).

The paper was published today (Wednesday 21 August) in Nature Communications, and could provide the first steps towards new treatments for neurodegenerative diseases.

What does the science tell us?

The clearance of cell wastes by autophagy is controlled by two things involving a protein called p62 -- firstly, a chemical process that sees p62 bind a number of identical molecules together (called oligomerisation), and secondly, p62's separation of molecules within cell fluid. The demixing process is called liquid-liquid phase separation (LLPS).

It is crucial to clarify how p62 LLPS is regulated in cells, and scientists have discovered that the process is facilitated by another protein called DAXX.

The study is the first to shed light on this particular protein interaction and its subsequent roles in autophagy and cell protection.

Providing new insights into autophagy, the research helps clarify a key process that might be faltering in those who develop dementia conditions.

What the scientists say

The study was led by Dr Shouqing Luo and his research group from the University of Plymouth's Institute of Translational and Stratified Medicine (ITSMed), in collaboration with Fudan University, Shanghai and Thomas Jefferson University, Philadelphia.

Dr Luo, whose work primarily focuses on finding new autophagy pathways, as well as novel treatments for dementia diseases -- using Huntington's Disease (HD) as a model -- said: "By understanding more about autophagy and the details of the processes involved, we can identify what might be going wrong, and therefore where to target when it comes to tackling neurodegenerative diseases. This research is a major step in helping us to do that.

"The next step for us is to look at applying the science within human cells, so we can further clarify how the protein interaction and the new DAXX function are relevant to neurodegenerative conditions including HD, and whether we can target it to help prevent disease progression.

"HD is an inherited disease that causes the progressive breakdown of nerve cells in the brain. It has a broad impact on a person's functional abilities and currently there is no cure, so it's vital that we continue our work to find out how and why the disease develops."

https://www.sciencedaily.com/releases/2019/08/190821082220.htm

Link between brain immune cells and Alzheimer's disease development identified

Absence of microglia prevents plaque formation

August 21, 2019

Science Daily/University of California - Irvine

Scientists from the University of California, Irvine School of Biological Sciences have discovered how to forestall Alzheimer's disease in a laboratory setting, a finding that could one day help in devising targeted drugs that prevent it.

The researchers found that by removing brain immune cells known as microglia from rodent models of Alzheimer's disease, beta-amyloid plaques -- the hallmark pathology of AD -- never formed. Their study will appear Aug. 21 in the journal Nature Communications.

Previous research has shown most Alzheimer's risk genes are turned on in microglia, suggesting these cells play a role in the disease. "However, we hadn't understood exactly what the microglia are doing and whether they are significant in the initial Alzheimer's process," said Kim Green, associate professor of neurobiology & behavior. "We decided to examine this issue by looking at what would happen in their absence."

The researchers used a drug that blocks microglia signaling that is necessary for their survival. Green and his lab have previously shown that blocking this signaling effectively eliminates these immune cells from the brain. "What was striking about these studies is we found that in areas without microglia, plaques didn't form," Green said. "However, in places where microglia survived, plaques did develop. You don't have Alzheimer's without plaques, and we now know microglia are a necessary component in the development of Alzheimer's."

The scientists also discovered that when plaques are present, microglia perceive them as harmful and attack them. However, the attack also switches off genes in neurons needed for normal brain functioning. "This finding underlines the crucial role of these brain immune cells in the development and progression of Alzheimer's," said Green.

Professor Green and colleagues say their discovery holds promise for creating future drugs that prevent the disease. "We are not proposing to remove all microglia from the brain," Professor Green said, noting the importance of microglia in regulating other brain functions. "What could be possible is devising therapeutics that affect microglia in targeted ways."

He also believes the project's research approach offers an avenue for better understanding other brain disorders.

"These immune cells are involved in every neurological disease and even in brain injury," Professor Green said. "Removing microglia could enable researchers working in those areas to determine the cells' role and whether targeting microglia could be a potential treatment."

https://www.sciencedaily.com/releases/2019/08/190821082236.htm